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APR Prediction Models
GAP (Generalized Aggregation Proneness)
ANuPP (Prediciton of Nucleating APRs)
V
L
AmY-Pred (Predicting antibody light chain aggregation)
Aggregation Kinetics Prediction Models
AggreRATE-Disc (Classifying Aggregating Point Mutation)
AggreRATE-Pred (Predicting Aggregation Rate for Point Mutation)
AbsoluRATE (Predicting Absolute aggregation rate)
Amylo-Pipe (Comprehensive aggregation prediction)
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APR Prediction Models:
GAP (Generalized Aggregation Proneness)
ANuPP (Prediciton of Nucleating APRs)
V
L
AmY-Pred (Predicting antibody light chain aggregation)
Aggregation Kinetics Prediction Models:
AggreRATE-Disc (Classifying Aggregating Point Mutation)
AggreRATE-Pred (Predicting Aggregation Rate for Point Mutation)
AbsoluRATE (Predicting Absolute aggregation rate)
Amylo-Pipe (Comprehensive aggregation prediction)
Structure database of aggregation related proteins and peptides
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Protein Name
Peptide Sequence
Entry ID
PDB ID
Method
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Aggregating complex
Inhibitor complex
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Displaying 61 to 90 records out of 565 records fetched.
Entry
PDB ID
Protein
Name
Species
Length
Mutation(s)
Class
Type
Method
Resolution (
Å
)
PMID
S-0061
1S9Z
Synthetic
18
No
Amyloid
Peptide
X-RAY DIFFRACTION
2.01
15070736
S-0062
1SAC
Serum amyloid P-component
Homo sapiens
204
No
Non-amyloid
Protein
X-RAY DIFFRACTION
2.0
8114934
S-0063
1SO8
3-hydroxyacyl-CoA dehydrogenase type-2
Homo sapiens
261
No
Amyloid
Protein complex
X-RAY DIFFRACTION
2.3
15087549
S-0064
1TIJ
Cystatin-C
Homo sapiens
120
L68Q, truncated fron N-terminal
Amyloid
Protein
X-RAY DIFFRACTION
3.03
16170782
S-0065
1TSH
Transthyretin
Homo sapiens
127
T60A
Amyloid
Protein
X-RAY DIFFRACTION
1.7
9818054
S-0066
1TT6
Transthyretin
Homo sapiens
127
No
Non-amyloid
Inhibitor complex
X-RAY DIFFRACTION
1.8
15469931
S-0067
1TZ8
Transthyretin
Homo sapiens
127
No
Non-amyloid
Inhibitor complex
X-RAY DIFFRACTION
1.85
15469931
S-0068
1U21
Transthyretin
Homo sapiens
127
No
Non-amyloid
Inhibitor complex
X-RAY DIFFRACTION
1.69
15826192
S-0069
1W08
Lysozyme C
Homo sapiens
130
T70N
Non-amyloid
Protein
X-RAY DIFFRACTION
2.5
16126226
S-0070
1X1P
Ribonuclease HII
Thermococcus kodakarensis
212
No
Amyloid
Aggregating complex
X-RAY DIFFRACTION
2.8
16367755
S-0071
1X7S
Transthyretin
Homo sapiens
127
Y78F
Amyloid
Protein
X-RAY DIFFRACTION
1.55
15735344
S-0072
1X7T
Transthyretin
Homo sapiens
127
R104H
Non-amyloid
Protein
X-RAY DIFFRACTION
1.6
15735344
S-0073
1XQ8
Alpha-synuclein
Homo sapiens
140
No
Amyloid
Protein complex
SOLUTION NMR
15615727
S-0074
1Y1D
Transthyretin
Homo sapiens
127
No
Non-amyloid
Inhibitor complex
X-RAY DIFFRACTION
1.7
15689188
S-0075
1YJO
Eukaryotic peptide chain release factor GTP-binding subunit
Saccharomyces cerevisiae
6
No
Amyloid
Fibril
X-RAY DIFFRACTION
1.3
15944695
S-0076
1YJP
Eukaryotic peptide chain release factor GTP-binding subunit
Saccharomyces cerevisiae
7
No
Amyloid
Fibril
X-RAY DIFFRACTION
1.8
15944695
S-0077
1Z0Q
Amyloid-beta A4 protein
Homo sapiens
42
No
Amyloid
Peptide
SOLUTION NMR
16444756
S-0078
1ZE7
Amyloid-beta A4 protein
Homo sapiens
18
No
Non-amyloid
Inhibitor complex
SOLUTION NMR
16301322
S-0079
1ZE9
Amyloid-beta A4 protein
Homo sapiens
18
No
Non-amyloid
Inhibitor complex
SOLUTION NMR
16301322
S-0080
2A3W
Serum amyloid P-component
Homo sapiens
204
No
Non-amyloid
Aggregating complex
X-RAY DIFFRACTION
2.2
16036920
S-0081
2A3X
Serum amyloid P-component
Homo sapiens
204
No
Non-amyloid
Aggregating complex
X-RAY DIFFRACTION
3.0
16036920
S-0082
2A3Y
Serum amyloid P-component
Homo sapiens
204
No
Non-amyloid
Aggregating complex
X-RAY DIFFRACTION
2.0
16036920
S-0083
2APQ
Ribonuclease pancreatic
Bos taurus
139
H119A
Amyloid
Protein
X-RAY DIFFRACTION
1.8
16148936
S-0084
2B14
Transthyretin
Homo sapiens
127
L55P
Non-amyloid
Inhibitor complex
X-RAY DIFFRACTION
2.0
16627944
S-0085
2B15
Transthyretin
Homo sapiens
127
No
Non-amyloid
Inhibitor complex
X-RAY DIFFRACTION
1.7
16627944
S-0086
2B16
Transthyretin
Homo sapiens
127
Y78F
Non-amyloid
Inhibitor complex
X-RAY DIFFRACTION
1.75
16627944
S-0087
2B77
Transthyretin
Homo sapiens
127
No
Non-amyloid
Inhibitor complex
X-RAY DIFFRACTION
1.7
14711308
S-0088
2B9A
Transthyretin
Homo sapiens
127
No
Non-amyloid
Inhibitor complex
X-RAY DIFFRACTION
1.54
14711308
S-0089
2BEG
Amyloid-beta A4 protein
Homo sapiens
42
No
Amyloid
Fibril
SOLUTION NMR
16293696
S-0090
2BFI
Synthetic
synthetic construct
12
No
Amyloid
FIbril
X-RAY DIFFRACTION
1.1
15630094
Entry:S-0061
PDB ID: 1S9Z
CSV
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Structure
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Protein Contacts Atlas
Sequence & Sec. Str.
Chain 1
1
X
S
I
R
E
L
E
A
R
I
R
E
L
E
L
R
I
G
18
Helix: Magenta; Strand: Yellow; Coil & Turn: White.
Charged residues and Proline are highlighed in blue.
Description
SYNTHETIC 17 AMINO ACID LONG PEPTIDE THAT FORMS A NATIVE-LIKE COILED-COIL AT AMBIENT TEMPERATURE AND AGGREGATES INTO AMYLOID-LIKE FIBRILS AT HIGHER TEMPERATURES.
A simplified peptide sequence designed de novo to fold into a coiled-coil conformation under ambient conditions but to transform into amyloid fibrils at elevated temperatures. The crystal structure of the coiled-coil form was determined and molecular model for the peptide in its fibrillar state was proposed. The relative stabilities of the two structural forms and the kinetics of their interconversion were found to be highly sensitive to small sequence changes.
Literature
PMID:
15070736
Author(s):
Kammerer, R.A., Kostrewa, D., Zurdo, J., Detken, A., Green, J.D., Meier, B.H., Winkler, F.K., Dobson, C.M., Steinmetz, M.O.
Reference:
Proc Natl Acad Sci U S A. 2004 Mar 30;101(13):4435-40. Epub 2004 Feb 26
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Entry:
CSV
JSON
Structure:
PDB
CIF
FASTA
Contact Network:
CSV
JSON
Protein Information
Protein Name:
Synthetic
Alternative Name:
Gene Name:
Sequence Length:
18
Species:
Mutation(s):
No
E.C. Number:
UniProt ID:
Keyword(s):
SYNTHETIC COILED-COIL PEPTIDE
Structure Information
PDB ID:
1S9Z
Amyloid Category:
Amyloid
Type:
Peptide
Global Stoichiometry:
Homo 3-mer - A3
PDB Classification:
DE NOVO PROTEIN
Method:
X-RAY DIFFRACTION
Resolution (
Å
):
2.01
R free:
0.233
Ligand Information
Ligand ID
Chain ID
Ligand Formula
Ligand MW
Ligand Name
Ligand SMILES
InChI Key
ACE
A
C2 H4 O
44.05
ACETYL GROUP
CC=O
IKHGUXGNUITLKF-UHFFFAOYSA-N
nan
A
Na 1
22.99
SODIUM ION
[Na+]
FKNQFGJONOIPTF-UHFFFAOYSA-N
ZN
A
Zn 2
65.41
ZINC ION
[Zn+2]
PTFCDOFLOPIGGS-UHFFFAOYSA-N
Entry:S-0062
PDB ID: 1SAC
CSV
JSON
Close ×
Structure
Press 'p' to pause
View interactive contact network
Protein Contacts Atlas
Sequence & Sec. Str.
Chain 1
1
H
T
D
L
S
G
K
V
F
V
F
P
R
E
S
V
T
D
H
V
N
L
I
T
P
25
26
L
E
K
P
L
Q
N
F
T
L
C
F
R
A
Y
S
D
L
S
R
A
Y
S
L
F
50
51
S
Y
N
T
Q
G
R
D
N
E
L
L
V
Y
K
E
R
V
G
E
Y
S
L
Y
I
75
76
G
R
H
K
V
T
S
K
V
I
E
K
F
P
A
P
V
H
I
C
V
S
W
E
S
100
101
S
S
G
I
A
E
F
W
I
N
G
T
P
L
V
K
K
G
L
R
Q
G
Y
F
V
125
126
E
A
Q
P
K
I
V
L
G
Q
E
Q
D
S
Y
G
G
K
F
D
R
S
Q
S
F
150
151
V
G
E
I
G
D
L
Y
M
W
D
S
V
L
P
P
E
N
I
L
S
A
Y
Q
G
175
176
T
P
L
P
A
N
I
L
D
W
Q
A
L
N
Y
E
I
R
G
Y
V
I
I
K
P
200
201
L
V
W
V
204
Chain 2
1
H
T
D
L
S
G
K
V
F
V
F
P
R
E
S
V
T
D
H
V
N
L
I
T
P
25
26
L
E
K
P
L
Q
N
F
T
L
C
F
R
A
Y
S
D
L
S
R
A
Y
S
L
F
50
51
S
Y
N
T
Q
G
R
D
N
E
L
L
V
Y
K
E
R
V
G
E
Y
S
L
Y
I
75
76
G
R
H
K
V
T
S
K
V
I
E
K
F
P
A
P
V
H
I
C
V
S
W
E
S
100
101
S
S
G
I
A
E
F
W
I
N
G
T
P
L
V
K
K
G
L
R
Q
G
Y
F
V
125
126
E
A
Q
P
K
I
V
L
G
Q
E
Q
D
S
Y
G
G
K
F
D
R
S
Q
S
F
150
151
V
G
E
I
G
D
L
Y
M
W
D
S
V
L
P
P
E
N
I
L
S
A
Y
Q
G
175
176
T
P
L
P
A
N
I
L
D
W
Q
A
L
N
Y
E
I
R
G
Y
V
I
I
K
P
200
201
L
V
W
V
204
Chain 3
1
H
T
D
L
S
G
K
V
F
V
F
P
R
E
S
V
T
D
H
V
N
L
I
T
P
25
26
L
E
K
P
L
Q
N
F
T
L
C
F
R
A
Y
S
D
L
S
R
A
Y
S
L
F
50
51
S
Y
N
T
Q
G
R
D
N
E
L
L
V
Y
K
E
R
V
G
E
Y
S
L
Y
I
75
76
G
R
H
K
V
T
S
K
V
I
E
K
F
P
A
P
V
H
I
C
V
S
W
E
S
100
101
S
S
G
I
A
E
F
W
I
N
G
T
P
L
V
K
K
G
L
R
Q
G
Y
F
V
125
126
E
A
Q
P
K
I
V
L
G
Q
E
Q
D
S
Y
G
G
K
F
D
R
S
Q
S
F
150
151
V
G
E
I
G
D
L
Y
M
W
D
S
V
L
P
P
E
N
I
L
S
A
Y
Q
G
175
176
T
P
L
P
A
N
I
L
D
W
Q
A
L
N
Y
E
I
R
G
Y
V
I
I
K
P
200
201
L
V
W
V
204
Chain 4
1
H
T
D
L
S
G
K
V
F
V
F
P
R
E
S
V
T
D
H
V
N
L
I
T
P
25
26
L
E
K
P
L
Q
N
F
T
L
C
F
R
A
Y
S
D
L
S
R
A
Y
S
L
F
50
51
S
Y
N
T
Q
G
R
D
N
E
L
L
V
Y
K
E
R
V
G
E
Y
S
L
Y
I
75
76
G
R
H
K
V
T
S
K
V
I
E
K
F
P
A
P
V
H
I
C
V
S
W
E
S
100
101
S
S
G
I
A
E
F
W
I
N
G
T
P
L
V
K
K
G
L
R
Q
G
Y
F
V
125
126
E
A
Q
P
K
I
V
L
G
Q
E
Q
D
S
Y
G
G
K
F
D
R
S
Q
S
F
150
151
V
G
E
I
G
D
L
Y
M
W
D
S
V
L
P
P
E
N
I
L
S
A
Y
Q
G
175
176
T
P
L
P
A
N
I
L
D
W
Q
A
L
N
Y
E
I
R
G
Y
V
I
I
K
P
200
201
L
V
W
V
204
Chain 5
1
H
T
D
L
S
G
K
V
F
V
F
P
R
E
S
V
T
D
H
V
N
L
I
T
P
25
26
L
E
K
P
L
Q
N
F
T
L
C
F
R
A
Y
S
D
L
S
R
A
Y
S
L
F
50
51
S
Y
N
T
Q
G
R
D
N
E
L
L
V
Y
K
E
R
V
G
E
Y
S
L
Y
I
75
76
G
R
H
K
V
T
S
K
V
I
E
K
F
P
A
P
V
H
I
C
V
S
W
E
S
100
101
S
S
G
I
A
E
F
W
I
N
G
T
P
L
V
K
K
G
L
R
Q
G
Y
F
V
125
126
E
A
Q
P
K
I
V
L
G
Q
E
Q
D
S
Y
G
G
K
F
D
R
S
Q
S
F
150
151
V
G
E
I
G
D
L
Y
M
W
D
S
V
L
P
P
E
N
I
L
S
A
Y
Q
G
175
176
T
P
L
P
A
N
I
L
D
W
Q
A
L
N
Y
E
I
R
G
Y
V
I
I
K
P
200
201
L
V
W
V
204
Helix: Magenta; Strand: Yellow; Coil & Turn: White.
Charged residues and Proline are highlighed in blue.
Description
THE STRUCTURE OF PENTAMERIC HUMAN SERUM AMYLOID P COMPONENT
Serum amyloid P component is a normal plasma protein and a universal non-fibrillar constituent of amyloid deposits. In the pathological situation, the binding of SAP to amyloid fibrils may be responsible. Protection could result simply from coating by SAP, which is completely unaltered with respect to its normal circulating form. Avaialbility of the SAP structure and its ligand binding site offer the opportunity for direct modelling of competitive inhibitor of SAP binding and producing binding site homologues (to be used as drugs).
Literature
PMID:
8114934
Author(s):
Emsley, J., White, H.E., O'Hara, B.P., Oliva, G., Srinivasan, N., Tickle, I.J., Blundell, T.L., Pepys, M.B., Wood, S.P.
Reference:
Nature. 1994 Jan 27;367(6461):338-45
Download
Entry:
CSV
JSON
Structure:
PDB
CIF
FASTA
Contact Network:
CSV
JSON
Protein Information
Protein Name:
Serum amyloid P-component
Alternative Name:
9.5S alpha-1-glycoprotein
Gene Name:
APCS, PTX2
Sequence Length:
204
Species:
Homo sapiens
Mutation(s):
No
E.C. Number:
UniProt ID:
P02743
Keyword(s):
SERUM AMYLOID P COMPONENT
Structure Information
PDB ID:
1SAC
Amyloid Category:
Non-amyloid
Type:
Protein
Global Stoichiometry:
Homo 5-mer - A5
PDB Classification:
AMYLOID PROTEIN
Method:
X-RAY DIFFRACTION
Resolution (
Å
):
2.0
R free:
Ligand Information
Ligand ID
Chain ID
Ligand Formula
Ligand MW
Ligand Name
Ligand SMILES
InChI Key
ACY
A
C2 H4 O2
60.05
ACETIC ACID
CC(=O)O
QTBSBXVTEAMEQO-UHFFFAOYSA-N
CA
A
Ca 2
40.08
CALCIUM ION
[Ca+2]
BHPQYMZQTOCNFJ-UHFFFAOYSA-N
ACY
B
C2 H4 O2
60.05
ACETIC ACID
CC(=O)O
QTBSBXVTEAMEQO-UHFFFAOYSA-N
CA
B
Ca 2
40.08
CALCIUM ION
[Ca+2]
BHPQYMZQTOCNFJ-UHFFFAOYSA-N
CA
C
Ca 2
40.08
CALCIUM ION
[Ca+2]
BHPQYMZQTOCNFJ-UHFFFAOYSA-N
ACY
D
C2 H4 O2
60.05
ACETIC ACID
CC(=O)O
QTBSBXVTEAMEQO-UHFFFAOYSA-N
CA
D
Ca 2
40.08
CALCIUM ION
[Ca+2]
BHPQYMZQTOCNFJ-UHFFFAOYSA-N
ACY
E
C2 H4 O2
60.05
ACETIC ACID
CC(=O)O
QTBSBXVTEAMEQO-UHFFFAOYSA-N
CA
E
Ca 2
40.08
CALCIUM ION
[Ca+2]
BHPQYMZQTOCNFJ-UHFFFAOYSA-N
Entry:S-0063
PDB ID: 1SO8
CSV
JSON
Close ×
Structure
Press 'p' to pause
View interactive contact network
Protein Contacts Atlas
Sequence & Sec. Str.
Chain 1
1
M
A
A
A
C
R
S
V
K
G
L
V
A
V
I
T
G
G
A
S
G
L
G
L
A
25
26
T
A
E
R
L
V
G
Q
G
A
S
A
V
L
L
D
L
P
N
S
G
G
E
A
Q
50
51
A
K
K
L
G
N
N
C
V
F
A
P
A
D
V
T
S
E
K
D
V
Q
T
A
L
75
76
A
L
A
K
G
K
F
G
R
V
D
V
A
V
N
C
A
G
I
A
V
A
S
K
T
100
101
Y
N
L
K
K
G
Q
T
H
T
L
E
D
F
Q
R
V
L
D
V
N
L
M
G
T
125
126
F
N
V
I
R
L
V
A
G
E
M
G
Q
N
E
P
D
Q
G
G
Q
R
G
V
I
150
151
I
N
T
A
S
V
A
A
F
E
G
Q
V
G
Q
A
A
Y
S
A
S
K
G
G
I
175
176
V
G
M
T
L
P
I
A
R
D
L
A
P
I
G
I
R
V
M
T
I
A
P
G
L
200
201
F
G
T
P
L
L
T
S
L
P
E
K
V
C
N
F
L
A
S
Q
V
P
F
P
S
225
226
R
L
G
D
P
A
E
Y
A
H
L
V
Q
A
I
I
E
N
P
F
L
N
G
E
V
250
251
I
R
L
D
G
A
I
R
M
Q
P
261
Helix: Magenta; Strand: Yellow; Coil & Turn: White.
Charged residues and Proline are highlighed in blue.
Description
Abeta-bound human ABAD structure
Demonstrated that ABeta-binding alcohol dehydrogenase (ABAD) is a direct molecular link from ABeta to mitochondrial toxicity. ABeta interacts with ABAD in the mitochondria of AD patients and transgenic mice. The crystal structure of ABeta-bound ABAD shows substantial deformation of the active site that prevents nicotinamide adenine dinucleotide (NAD) binding. An ABAD peptide specifically inhibits ABAD-ABeta interaction and suppresses ABeta-induced apoptosis and free-radical generation in neurons.
Literature
PMID:
15087549
Author(s):
Lustbader, J.W., Cirilli, M., Lin, C., Xu, H.W., Takuma, K., Wang, N., Caspersen, C., Chen, X., Pollak, S., Chaney, M., Trinchese, F., Gunn-Moore, F., Lue, L.F., Walker, D.G., Kuppusamy, P., Zewier, Z.L., Arancio, O., Stern, D., Yan, S.S., Wu, H.
Reference:
Science. 2004 Apr 16;304(5669):448-52
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Structure:
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Contact Network:
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Protein Information
Protein Name:
3-hydroxyacyl-CoA dehydrogenase type-2
Alternative Name:
17-beta-hydroxysteroid dehydrogenase 10, 2-methyl-3-hydroxybutyryl-CoA dehydrogenase, 3-hydroxy-2-methylbutyryl-CoA dehydrogenase, 3-hydroxyacyl-CoA dehydrogenase type II, Endoplasmic reticulum-associated amyloid beta-peptide-binding protein, Mitochondria
Gene Name:
HSD17B10, ERAB, HADH2, MRPP2, SCHAD, SDR5C1, XH98G2
Sequence Length:
261
Species:
Homo sapiens
Mutation(s):
No
E.C. Number:
1.1.1.35
UniProt ID:
Q99714
Keyword(s):
3-hydroxyacyl-CoA dehydrogenase type II
Structure Information
PDB ID:
1SO8
Amyloid Category:
Amyloid
Type:
Protein complex
Global Stoichiometry:
Homo 4-mer - A4
PDB Classification:
OXIDOREDUCTASE
Method:
X-RAY DIFFRACTION
Resolution (
Å
):
2.3
R free:
0.261
Ligand Information
Ligand ID
Chain ID
Ligand Formula
Ligand MW
Ligand Name
Ligand SMILES
InChI Key
CL
A
Cl -1
35.45
CHLORIDE ION
[Cl-]
VEXZGXHMUGYJMC-UHFFFAOYSA-M
nan
A
Na 1
22.99
SODIUM ION
[Na+]
FKNQFGJONOIPTF-UHFFFAOYSA-N
Entry:S-0064
PDB ID: 1TIJ
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Structure
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Protein Contacts Atlas
Sequence & Sec. Str.
Chain 1
1
S
S
P
G
K
P
P
R
L
V
G
G
P
M
D
A
S
V
E
E
E
G
V
R
R
25
26
A
L
D
F
A
V
G
E
Y
N
K
A
S
N
D
M
Y
H
S
R
A
L
Q
V
V
50
51
R
A
R
K
Q
I
V
A
G
V
N
Y
F
L
D
V
E
L
G
R
T
T
C
T
K
75
76
T
Q
P
N
L
D
N
C
P
F
H
D
Q
P
H
L
K
R
K
A
F
C
S
F
Q
100
101
I
Y
A
V
P
W
Q
G
T
M
T
L
S
K
S
T
C
Q
D
A
120
Chain 2
1
S
S
P
G
K
P
P
R
L
V
G
G
P
M
D
A
S
V
E
E
E
G
V
R
R
25
26
A
L
D
F
A
V
G
E
Y
N
K
A
S
N
D
M
Y
H
S
R
A
L
Q
V
V
50
51
R
A
R
K
Q
I
V
A
G
V
N
Y
F
L
D
V
E
L
G
R
T
T
C
T
K
75
76
T
Q
P
N
L
D
N
C
P
F
H
D
Q
P
H
L
K
R
K
A
F
C
S
F
Q
100
101
I
Y
A
V
P
W
Q
G
T
M
T
L
S
K
S
T
C
Q
D
A
120
Helix: Magenta; Strand: Yellow; Coil & Turn: White.
Charged residues and Proline are highlighed in blue.
Description
3D Domain-swapped human cystatin C with amyloid-like intermolecular beta-sheets
Oligomerization of human cystatin C (HCC) leads to amyloid deposits in brain arteries, and this process is greatly accelerated with a naturally occurring L68Q variant. The crystal structures of N-truncated and full-length HCC showed dimer formation via (3D) domain swapping which could be the basis of HCC fibril formation.
Literature
PMID:
16170782
Author(s):
Janowski, R., Kozak, M., Abrahamson, M., Grubb, A., Jaskolski, M.
Reference:
Proteins. 2005 Nov 15;61(3):570-8
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Structure:
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Contact Network:
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Protein Information
Protein Name:
Cystatin-C
Alternative Name:
Cystatin-3, Gamma-trace, Neuroendocrine basic polypeptide, Post-gamma-globulin
Gene Name:
CST3
Sequence Length:
120
Species:
Homo sapiens
Mutation(s):
L68Q, truncated fron N-terminal
E.C. Number:
UniProt ID:
P01034
Keyword(s):
Cystatin C
Structure Information
PDB ID:
1TIJ
Amyloid Category:
Amyloid
Type:
Protein
Global Stoichiometry:
Homo 2-mer - A2
PDB Classification:
HYDROLASE INHIBITOR
Method:
X-RAY DIFFRACTION
Resolution (
Å
):
3.03
R free:
0.262
Entry:S-0065
PDB ID: 1TSH
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JSON
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Structure
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Protein Contacts Atlas
Sequence & Sec. Str.
Chain 1
1
G
P
T
G
T
G
E
S
K
C
P
L
M
V
K
V
L
D
A
V
R
G
S
P
A
25
26
I
N
V
A
V
H
V
F
R
K
A
A
D
D
T
W
E
P
F
A
S
G
K
T
S
50
51
E
S
G
E
L
H
G
L
T
A
E
E
E
F
V
E
G
I
Y
K
V
E
I
D
T
75
76
K
S
Y
W
K
A
L
G
I
S
P
F
H
E
H
A
E
V
V
F
T
A
N
D
S
100
101
G
P
R
R
Y
T
I
A
A
L
L
S
P
Y
S
Y
S
T
T
A
V
V
T
N
P
125
126
K
E
127
Chain 2
1
G
P
T
G
T
G
E
S
K
C
P
L
M
V
K
V
L
D
A
V
R
G
S
P
A
25
26
I
N
V
A
V
H
V
F
R
K
A
A
D
D
T
W
E
P
F
A
S
G
K
T
S
50
51
E
S
G
E
L
H
G
L
T
A
E
E
E
F
V
E
G
I
Y
K
V
E
I
D
T
75
76
K
S
Y
W
K
A
L
G
I
S
P
F
H
E
H
A
E
V
V
F
T
A
N
D
S
100
101
G
P
R
R
Y
T
I
A
A
L
L
S
P
Y
S
Y
S
T
T
A
V
V
T
N
P
125
126
K
E
127
Helix: Magenta; Strand: Yellow; Coil & Turn: White.
Charged residues and Proline are highlighed in blue.
Description
TERTIARY STRUCTURES OF THREE AMYLOIDOGENIC TRANSTHYRETIN VARIANTS AND IMPLICATIONS FOR AMYLOID FIBRIL FORMATION
They reported crystallization and structural investigations of three amyloidogenic (Arg10, Ala60, Tyr77) and two non-amyloidogenic variants (Ser6, Met119). The similarity of these structures to normal transthyretin does not give direct clues to the fibril forming process. All amyloidogenic variants show an increased main chain solvent exposure when compared to normal transthyretin and non-amyloidogenic variants, which can be postulated to result in increased susceptibility to proteolysis.
Literature
PMID:
9818054
Author(s):
Schormann, N., Murrell, J.R., Benson, M.D.
Reference:
Amyloid. 1998 Sep;5(3):175-87
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Entry:
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Contact Network:
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Protein Information
Protein Name:
Transthyretin
Alternative Name:
ATTR, Prealbumin, TBPA
Gene Name:
TTR, PALB
Sequence Length:
127
Species:
Homo sapiens
Mutation(s):
T60A
E.C. Number:
UniProt ID:
P02766
Keyword(s):
TRANSTHYRETIN
Structure Information
PDB ID:
1TSH
Amyloid Category:
Amyloid
Type:
Protein
Global Stoichiometry:
Homo 4-mer - A4
PDB Classification:
TRANSPORT
Method:
X-RAY DIFFRACTION
Resolution (
Å
):
1.7
R free:
0.248
Entry:S-0066
PDB ID: 1TT6
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Protein Contacts Atlas
Sequence & Sec. Str.
Chain 1
1
G
P
T
G
T
G
E
S
K
C
P
L
M
V
K
V
L
D
A
V
R
G
S
P
A
25
26
I
N
V
A
V
H
V
F
R
K
A
A
D
D
T
W
E
P
F
A
S
G
K
T
S
50
51
E
S
G
E
L
H
G
L
T
T
E
E
E
F
V
E
G
I
Y
K
V
E
I
D
T
75
76
K
S
Y
W
K
A
L
G
I
S
P
F
H
E
H
A
E
V
V
F
T
A
N
D
S
100
101
G
P
R
R
Y
T
I
A
A
L
L
S
P
Y
S
Y
S
T
T
A
V
V
T
N
P
125
126
K
E
127
Chain 2
1
G
P
T
G
T
G
E
S
K
C
P
L
M
V
K
V
L
D
A
V
R
G
S
P
A
25
26
I
N
V
A
V
H
V
F
R
K
A
A
D
D
T
W
E
P
F
A
S
G
K
T
S
50
51
E
S
G
E
L
H
G
L
T
T
E
E
E
F
V
E
G
I
Y
K
V
E
I
D
T
75
76
K
S
Y
W
K
A
L
G
I
S
P
F
H
E
H
A
E
V
V
F
T
A
N
D
S
100
101
G
P
R
R
Y
T
I
A
A
L
L
S
P
Y
S
Y
S
T
T
A
V
V
T
N
P
125
126
K
E
127
Helix: Magenta; Strand: Yellow; Coil & Turn: White.
Charged residues and Proline are highlighed in blue.
Description
The crystal structure of transthyretin in complex with diethylstilbestrol
"""The orthorhombic crystal structure of transthyretin in complex with diethylstilbestrol"". The crystallographic study of DES binding to TTR. The structural data reveal two different binding modes, both located in the thyroxine binding channel. In both cases, DES binds deeply in the channel and establishes interactions with the equivalent molecule present in the adjacent binding site. The most remarkable features of DES interaction with TTR are its hydrophobic interactions within the protein halogen binding pockets, where its ethyl groups are snugly fitted, and the hydrogen bonds established at the center of the tetramer with Ser-117. "
Literature
PMID:
15469931
Author(s):
Morais-de-Sa, E., Pereira, P.J.B., Saraiva, M.J., Damas, A.M.
Reference:
J Biol Chem. 2004 Dec 17;279(51):53483-90. Epub 2004 Oct 6
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Entry:
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Structure:
PDB
CIF
FASTA
Contact Network:
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JSON
Protein Information
Protein Name:
Transthyretin
Alternative Name:
ATTR, Prealbumin, TBPA
Gene Name:
TTR, PALB
Sequence Length:
127
Species:
Homo sapiens
Mutation(s):
No
E.C. Number:
UniProt ID:
P02766
Keyword(s):
Transthyretin
Structure Information
PDB ID:
1TT6
Amyloid Category:
Non-amyloid
Type:
Inhibitor complex
Global Stoichiometry:
Homo 4-mer - A4
PDB Classification:
TRANSPORT PROTEIN
Method:
X-RAY DIFFRACTION
Resolution (
Å
):
1.8
R free:
0.218
Ligand Information
Ligand ID
Chain ID
Ligand Formula
Ligand MW
Ligand Name
Ligand SMILES
InChI Key
DES
A
C18 H20 O2
268.35
DIETHYLSTILBESTROL
CC/C(=C(/CC)c1ccc(cc1)O)/c2ccc(cc2)O
RGLYKWWBQGJZGM-ISLYRVAYSA-N
GOL
A
C3 H8 O3
92.09
GLYCEROL
C(C(CO)O)O
PEDCQBHIVMGVHV-UHFFFAOYSA-N
SO4
A
O4 S -2
96.06
SULFATE ION
[O-]S(=O)(=O)[O-]
QAOWNCQODCNURD-UHFFFAOYSA-L
DES
B
C18 H20 O2
268.35
DIETHYLSTILBESTROL
CC/C(=C(/CC)c1ccc(cc1)O)/c2ccc(cc2)O
RGLYKWWBQGJZGM-ISLYRVAYSA-N
Entry:S-0067
PDB ID: 1TZ8
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Structure
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Protein Contacts Atlas
Sequence & Sec. Str.
Chain 1
1
G
P
T
G
T
G
E
S
K
C
P
L
M
V
K
V
L
D
A
V
R
G
S
P
A
25
26
I
N
V
A
V
H
V
F
R
K
A
A
D
D
T
W
E
P
F
A
S
G
K
T
S
50
51
E
S
G
E
L
H
G
L
T
T
E
E
E
F
V
E
G
I
Y
K
V
E
I
D
T
75
76
K
S
Y
W
K
A
L
G
I
S
P
F
H
E
H
A
E
V
V
F
T
A
N
D
S
100
101
G
P
R
R
Y
T
I
A
A
L
L
S
P
Y
S
Y
S
T
T
A
V
V
T
N
P
125
126
K
E
127
Chain 2
1
G
P
T
G
T
G
E
S
K
C
P
L
M
V
K
V
L
D
A
V
R
G
S
P
A
25
26
I
N
V
A
V
H
V
F
R
K
A
A
D
D
T
W
E
P
F
A
S
G
K
T
S
50
51
E
S
G
E
L
H
G
L
T
T
E
E
E
F
V
E
G
I
Y
K
V
E
I
D
T
75
76
K
S
Y
W
K
A
L
G
I
S
P
F
H
E
H
A
E
V
V
F
T
A
N
D
S
100
101
G
P
R
R
Y
T
I
A
A
L
L
S
P
Y
S
Y
S
T
T
A
V
V
T
N
P
125
126
K
E
127
Chain 3
1
G
P
T
G
T
G
E
S
K
C
P
L
M
V
K
V
L
D
A
V
R
G
S
P
A
25
26
I
N
V
A
V
H
V
F
R
K
A
A
D
D
T
W
E
P
F
A
S
G
K
T
S
50
51
E
S
G
E
L
H
G
L
T
T
E
E
E
F
V
E
G
I
Y
K
V
E
I
D
T
75
76
K
S
Y
W
K
A
L
G
I
S
P
F
H
E
H
A
E
V
V
F
T
A
N
D
S
100
101
G
P
R
R
Y
T
I
A
A
L
L
S
P
Y
S
Y
S
T
T
A
V
V
T
N
P
125
126
K
E
127
Chain 4
1
G
P
T
G
T
G
E
S
K
C
P
L
M
V
K
V
L
D
A
V
R
G
S
P
A
25
26
I
N
V
A
V
H
V
F
R
K
A
A
D
D
T
W
E
P
F
A
S
G
K
T
S
50
51
E
S
G
E
L
H
G
L
T
T
E
E
E
F
V
E
G
I
Y
K
V
E
I
D
T
75
76
K
S
Y
W
K
A
L
G
I
S
P
F
H
E
H
A
E
V
V
F
T
A
N
D
S
100
101
G
P
R
R
Y
T
I
A
A
L
L
S
P
Y
S
Y
S
T
T
A
V
V
T
N
P
125
126
K
E
127
Helix: Magenta; Strand: Yellow; Coil & Turn: White.
Charged residues and Proline are highlighed in blue.
Description
The crystal structure of transthyretin in complex with diethylstilbestrol
"""The monoclinic crystal structure of transthyretin in complex with diethylstilbestrol"". The crystallographic study of DES binding to TTR. The structural data reveal two different binding modes, both located in the thyroxine binding channel. In both cases, DES binds deeply in the channel and establishes interactions with the equivalent molecule present in the adjacent binding site. The most remarkable features of DES interaction with TTR are its hydrophobic interactions within the protein halogen binding pockets, where its ethyl groups are snugly fitted, and the hydrogen bonds established at the center of the tetramer with Ser-117. "
Literature
PMID:
15469931
Author(s):
Morais-de-Sa, E.M., Pereira, P.J.B., Saraiva, M.J., Damas, A.M.
Reference:
J Biol Chem. 2004 Dec 17;279(51):53483-90. Epub 2004 Oct 6
Download
Entry:
CSV
JSON
Structure:
PDB
CIF
FASTA
Contact Network:
CSV
JSON
Protein Information
Protein Name:
Transthyretin
Alternative Name:
ATTR, Prealbumin, TBPA
Gene Name:
TTR, PALB
Sequence Length:
127
Species:
Homo sapiens
Mutation(s):
No
E.C. Number:
UniProt ID:
P02766
Keyword(s):
Transthyretin
Structure Information
PDB ID:
1TZ8
Amyloid Category:
Non-amyloid
Type:
Inhibitor complex
Global Stoichiometry:
Homo 4-mer - A4
PDB Classification:
TRANSPORT PROTEIN
Method:
X-RAY DIFFRACTION
Resolution (
Å
):
1.85
R free:
0.221
Ligand Information
Ligand ID
Chain ID
Ligand Formula
Ligand MW
Ligand Name
Ligand SMILES
InChI Key
ACT
A
C2 H3 O2 -1
59.04
ACETATE ION
CC(=O)[O-]
QTBSBXVTEAMEQO-UHFFFAOYSA-M
DMS
A
C2 H6 O S
78.13
DIMETHYL SULFOXIDE
CS(=O)C
IAZDPXIOMUYVGZ-UHFFFAOYSA-N
GOL
A
C3 H8 O3
92.09
GLYCEROL
C(C(CO)O)O
PEDCQBHIVMGVHV-UHFFFAOYSA-N
DES
B
C18 H20 O2
268.35
DIETHYLSTILBESTROL
CC/C(=C(/CC)c1ccc(cc1)O)/c2ccc(cc2)O
RGLYKWWBQGJZGM-ISLYRVAYSA-N
CO3
C
C O3 -2
60.01
CARBONATE ION
C(=O)([O-])[O-]
BVKZGUZCCUSVTD-UHFFFAOYSA-L
DES
C
C18 H20 O2
268.35
DIETHYLSTILBESTROL
CC/C(=C(/CC)c1ccc(cc1)O)/c2ccc(cc2)O
RGLYKWWBQGJZGM-ISLYRVAYSA-N
DES
D
C18 H20 O2
268.35
DIETHYLSTILBESTROL
CC/C(=C(/CC)c1ccc(cc1)O)/c2ccc(cc2)O
RGLYKWWBQGJZGM-ISLYRVAYSA-N
GOL
D
C3 H8 O3
92.09
GLYCEROL
C(C(CO)O)O
PEDCQBHIVMGVHV-UHFFFAOYSA-N
Entry:S-0068
PDB ID: 1U21
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Protein Contacts Atlas
Sequence & Sec. Str.
Chain 1
1
G
P
T
G
T
G
E
S
K
C
P
L
M
V
K
V
L
D
A
V
R
G
S
P
A
25
26
I
N
V
A
V
H
V
F
R
K
A
A
D
D
T
W
E
P
F
A
S
G
K
T
S
50
51
E
S
G
E
L
H
G
L
T
T
E
E
E
F
V
E
G
I
Y
K
V
E
I
D
T
75
76
K
S
Y
W
K
A
L
G
I
S
P
F
H
E
H
A
E
V
V
F
T
A
N
D
S
100
101
G
P
R
R
Y
T
I
A
A
L
L
S
P
Y
S
Y
S
T
T
A
V
V
T
N
P
125
126
K
E
127
Chain 2
1
G
P
T
G
T
G
E
S
K
C
P
L
M
V
K
V
L
D
A
V
R
G
S
P
A
25
26
I
N
V
A
V
H
V
F
R
K
A
A
D
D
T
W
E
P
F
A
S
G
K
T
S
50
51
E
S
G
E
L
H
G
L
T
T
E
E
E
F
V
E
G
I
Y
K
V
E
I
D
T
75
76
K
S
Y
W
K
A
L
G
I
S
P
F
H
E
H
A
E
V
V
F
T
A
N
D
S
100
101
G
P
R
R
Y
T
I
A
A
L
L
S
P
Y
S
Y
S
T
T
A
V
V
T
N
P
125
126
K
E
127
Helix: Magenta; Strand: Yellow; Coil & Turn: White.
Charged residues and Proline are highlighed in blue.
Description
transthyretin with tethered inhibitor on one monomer.
Transthyretin (TTR) amyloidogenesis requires rate-limiting tetramer dissociation before misassembly of a partially denatured monomer ensues. Selective stabilization of the native TTR tetramer over the dissociative transition state by small molecule binding to both thyroxine binding sites raises the kinetic barrier of tetramer dissociation, preventing amyloidogenesis. Here, one fibril formation inhibitor tether to TTR by disulfide bond formation. Occupancy of only one of the two thyroxine binding sites is sufficient to inhibit tetramer dissociation in 6.0 M urea and amyloidogenesis under acidic conditions by imposing kinetic stabilization on the entire tetramer.
Literature
PMID:
15826192
Author(s):
Wiseman, R.L., Johnson, S.M., Kelker, M.S., Foss, T., Wilson, I.A., Kelly, J.W.
Reference:
J Am Chem Soc. 2005 Apr 20;127(15):5540-51
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Protein Information
Protein Name:
Transthyretin
Alternative Name:
ATTR, Prealbumin, TBPA
Gene Name:
TTR, PALB
Sequence Length:
127
Species:
Homo sapiens
Mutation(s):
No
E.C. Number:
UniProt ID:
P02766
Keyword(s):
Transthyretin
Structure Information
PDB ID:
1U21
Amyloid Category:
Non-amyloid
Type:
Inhibitor complex
Global Stoichiometry:
Homo 4-mer - A5
PDB Classification:
HORMONE/GROWTH FACTOR
Method:
X-RAY DIFFRACTION
Resolution (
Å
):
1.69
R free:
0.239
Ligand Information
Ligand ID
Chain ID
Ligand Formula
Ligand MW
Ligand Name
Ligand SMILES
InChI Key
P2C
A
C13 H9 Cl2 N O5
330.12
2-[(3,5-DICHLORO-4-TRIOXIDANYLPHENYL)AMINO]BENZOIC ACID
c1ccc(c(c1)C(=O)O)Nc2cc(c(c(c2)Cl)OOO)Cl
SNAMTVTZDPUVRA-UHFFFAOYSA-N
P2C
B
C13 H9 Cl2 N O5
330.12
2-[(3,5-DICHLORO-4-TRIOXIDANYLPHENYL)AMINO]BENZOIC ACID
c1ccc(c(c1)C(=O)O)Nc2cc(c(c(c2)Cl)OOO)Cl
SNAMTVTZDPUVRA-UHFFFAOYSA-N
Entry:S-0069
PDB ID: 1W08
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Protein Contacts Atlas
Sequence & Sec. Str.
Chain 1
1
K
V
F
E
R
C
E
L
A
R
T
L
K
R
L
G
M
D
G
Y
R
G
I
S
L
25
26
A
N
W
M
C
L
A
K
W
E
S
G
Y
N
T
R
A
T
N
Y
N
A
G
D
R
50
51
S
T
D
Y
G
I
F
Q
I
N
S
R
Y
W
C
N
D
G
K
N
P
G
A
V
N
75
76
A
C
H
L
S
C
S
A
L
L
Q
D
N
I
A
D
A
V
A
C
A
K
R
V
V
100
101
R
D
P
Q
G
I
R
A
W
V
A
W
R
N
R
C
Q
N
R
D
V
R
Q
Y
V
125
126
Q
G
C
G
V
130
Helix: Magenta; Strand: Yellow; Coil & Turn: White.
Charged residues and Proline are highlighed in blue.
Description
T70N human lysozyme is the only known naturally occurring destabilised lysozyme variant that has not been detected in amyloid deposits in human patients
T70N human lysozyme is the only known naturally occurring destabilised lysozyme variant that has not been detected in amyloid deposits in human patients. The X-ray crystal structure shows that a substantial structural rearrangement results from the amino acid substitution, involving residues 45-51 and 68-75 in particular, and gives rise to a concomitant separation of these two loops of up to 6.5A. For residues 70-74, shows that the T70N substitution increases the flexibility of the peptide backbone around the site of mutation.
Literature
PMID:
16126226
Author(s):
Johnson, R., Christodoulou, J., Dumoulin, M., Caddy, G., Alcocer, M., Murtagh, G., Kumita, J.R., Larsson, G., Robinson, C.V., Archer, D.B., Luisi, B., Dobson, C.M.
Reference:
J Mol Biol. 2005 Sep 30;352(4):823-36
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Protein Information
Protein Name:
Lysozyme C
Alternative Name:
1, 4-beta-N-acetylmuramidase C
Gene Name:
LYZ, LZM
Sequence Length:
130
Species:
Homo sapiens
Mutation(s):
T70N
E.C. Number:
3.2.1.17
UniProt ID:
P61626
Keyword(s):
LYSOZYME
Structure Information
PDB ID:
1W08
Amyloid Category:
Non-amyloid
Type:
Protein
Global Stoichiometry:
Monomer - A
PDB Classification:
HYDROLASE
Method:
X-RAY DIFFRACTION
Resolution (
Å
):
2.5
R free:
0.268
Ligand Information
Ligand ID
Chain ID
Ligand Formula
Ligand MW
Ligand Name
Ligand SMILES
InChI Key
CL
A
Cl -1
35.45
CHLORIDE ION
[Cl-]
VEXZGXHMUGYJMC-UHFFFAOYSA-M
Entry:S-0070
PDB ID: 1X1P
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Sequence & Sec. Str.
Chain 1
1
M
K
I
A
G
I
D
E
A
G
R
G
P
V
I
G
P
M
V
I
A
A
V
V
V
25
26
D
E
N
S
L
P
K
L
E
E
L
K
V
R
D
S
K
K
L
T
P
K
R
R
E
50
51
K
L
F
N
E
I
L
G
V
L
D
D
Y
V
I
L
E
L
P
P
D
V
I
G
S
75
76
R
E
G
T
L
N
E
F
E
V
E
N
F
A
K
A
L
N
S
L
K
V
K
P
D
100
101
V
I
Y
A
D
A
A
D
V
D
E
E
R
F
A
R
E
L
G
E
R
L
N
F
E
125
126
A
E
V
V
A
K
H
K
A
D
D
I
F
P
V
V
S
A
A
S
I
L
A
K
V
150
151
T
R
D
R
A
V
E
K
L
K
E
E
Y
G
E
I
G
S
G
Y
P
S
D
P
R
175
176
T
R
A
F
L
E
N
Y
Y
R
E
H
G
E
F
P
P
I
V
R
K
G
A
G
A
200
201
I
I
G
L
A
V
G
G
V
V
I
A
212
Helix: Magenta; Strand: Yellow; Coil & Turn: White.
Charged residues and Proline are highlighed in blue.
Description
Crystal structure of Tk-RNase HII(1-197)-A(28-42)
"""Crystal structure of Tk-RNase HII(1-197)-A(28-42)"". The atomic-level structure of ABeta(28-42) in an aqueous environment. The fragments of ABeta, residues 10-24 or 28-42 were fused to three positions in the C-terminal region of ribonuclease HII from a hyperthermophile (Tk-RNase HII) and examined for structural properties in an aqueous environment. Tk-RNase HII is highly stable and the C-terminal region has relatively little interaction with other parts. The guest amyloidogenic sequences did not affect the overall structure of the Tk-RNase HII. Crystal structure analysis of Tk-RNase HII(1-197)-ABeta(28-42) revealed that ABeta(28-42) forms a Beta conformation, whereas the original structure in Tk-RNase HII(1-213) was Alpha helix, suggesting Beta-structure formation of ABeta(28-42) within full-length ABeta in aqueous solution. ABeta(28-42) enhanced aggregation of the host protein more strongly than ABeta(10-24)."
Literature
PMID:
16367755
Author(s):
Takano, K., Endo, S., Mukaiyama, A., Chon, H., Matsumura, H., Koga, Y., Kanaya, S.
Reference:
FEBS J. 2006 Jan;273(1):150-8
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Protein Information
Protein Name:
Ribonuclease HII
Alternative Name:
Gene Name:
rnhB, TK0805
Sequence Length:
212
Species:
Thermococcus kodakarensis
Mutation(s):
No
E.C. Number:
3.1.26.4
UniProt ID:
O74035
Keyword(s):
Ribonuclease HII
Structure Information
PDB ID:
1X1P
Amyloid Category:
Amyloid
Type:
Aggregating complex
Global Stoichiometry:
Monomer - A
PDB Classification:
HYDROLASE
Method:
X-RAY DIFFRACTION
Resolution (
Å
):
2.8
R free:
0.3
Entry:S-0071
PDB ID: 1X7S
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Sequence & Sec. Str.
Chain 1
1
G
P
T
G
T
G
E
S
K
C
P
L
M
V
K
V
L
D
A
V
R
G
S
P
A
25
26
I
N
V
A
V
H
V
F
R
K
A
A
D
D
T
W
E
P
F
A
S
G
K
T
S
50
51
E
S
G
E
L
H
G
L
T
T
E
E
E
F
V
E
G
I
Y
K
V
E
I
D
T
75
76
K
S
F
W
K
A
L
G
I
S
P
F
H
E
H
A
E
V
V
F
T
A
N
D
S
100
101
G
P
R
R
Y
T
I
A
A
L
L
S
P
Y
S
Y
S
T
T
A
V
V
T
N
P
125
126
K
E
127
Chain 2
1
G
P
T
G
T
G
E
S
K
C
P
L
M
V
K
V
L
D
A
V
R
G
S
P
A
25
26
I
N
V
A
V
H
V
F
R
K
A
A
D
D
T
W
E
P
F
A
S
G
K
T
S
50
51
E
S
G
E
L
H
G
L
T
T
E
E
E
F
V
E
G
I
Y
K
V
E
I
D
T
75
76
K
S
F
W
K
A
L
G
I
S
P
F
H
E
H
A
E
V
V
F
T
A
N
D
S
100
101
G
P
R
R
Y
T
I
A
A
L
L
S
P
Y
S
Y
S
T
T
A
V
V
T
N
P
125
126
K
E
127
Helix: Magenta; Strand: Yellow; Coil & Turn: White.
Charged residues and Proline are highlighed in blue.
Description
The X-ray crystallographic structure of the amyloidogenic variant TTR Tyr78Phe
The analysis of the protein model for TTR Y78F indicates a destabilization of the contacts between the Alpha-helix and AB loop and the body of the molecule, intimately related to the amyloidogenic nature
Literature
PMID:
15735344
Author(s):
Neto-Silva, R.M., Macedo-Ribeiro, S., Pereira, P.J., Coll, M., Saraiva, M.J., Damas, A.M.
Reference:
Acta Crystallogr D Biol Crystallogr. 2005 Mar;61(Pt 3):333-9. Epub 2005 Feb 24
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Protein Information
Protein Name:
Transthyretin
Alternative Name:
ATTR, Prealbumin, TBPA
Gene Name:
TTR, PALB
Sequence Length:
127
Species:
Homo sapiens
Mutation(s):
Y78F
E.C. Number:
UniProt ID:
P02766
Keyword(s):
Transthyretin
Structure Information
PDB ID:
1X7S
Amyloid Category:
Amyloid
Type:
Protein
Global Stoichiometry:
Homo 4-mer - A4
PDB Classification:
TRANSPORT PROTEIN
Method:
X-RAY DIFFRACTION
Resolution (
Å
):
1.55
R free:
0.23800000
Entry:S-0072
PDB ID: 1X7T
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Sequence & Sec. Str.
Chain 1
1
G
P
T
G
T
G
E
S
K
C
P
L
M
V
K
V
L
D
A
V
R
G
S
P
A
25
26
I
N
V
A
V
H
V
F
R
K
A
A
D
D
T
W
E
P
F
A
S
G
K
T
S
50
51
E
S
G
E
L
H
G
L
T
T
E
E
E
F
V
E
G
I
Y
K
V
E
I
D
T
75
76
K
S
Y
W
K
A
L
G
I
S
P
F
H
E
H
A
E
V
V
F
T
A
N
D
S
100
101
G
P
R
H
Y
T
I
A
A
L
L
S
P
Y
S
Y
S
T
T
A
V
V
T
N
P
125
126
K
E
127
Chain 2
1
G
P
T
G
T
G
E
S
K
C
P
L
M
V
K
V
L
D
A
V
R
G
S
P
A
25
26
I
N
V
A
V
H
V
F
R
K
A
A
D
D
T
W
E
P
F
A
S
G
K
T
S
50
51
E
S
G
E
L
H
G
L
T
T
E
E
E
F
V
E
G
I
Y
K
V
E
I
D
T
75
76
K
S
Y
W
K
A
L
G
I
S
P
F
H
E
H
A
E
V
V
F
T
A
N
D
S
100
101
G
P
R
H
Y
T
I
A
A
L
L
S
P
Y
S
Y
S
T
T
A
V
V
T
N
P
125
126
K
E
127
Helix: Magenta; Strand: Yellow; Coil & Turn: White.
Charged residues and Proline are highlighed in blue.
Description
a non-amyloidogenic variant with protective clinical effects
In the TTR R104H variant new contacts involving the N-terminal region and His104 are antagonists of amyloid formation.
Literature
PMID:
15735344
Author(s):
Neto-Silva, R.M., Macedo-Ribeiro, S., Pereira, P.J., Coll, M., Saraiva, M.J., Damas, A.M.
Reference:
Acta Crystallogr D Biol Crystallogr. 2005 Mar;61(Pt 3):333-9. Epub 2005 Feb 24
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Contact Network:
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Protein Information
Protein Name:
Transthyretin
Alternative Name:
ATTR, Prealbumin, TBPA
Gene Name:
TTR, PALB
Sequence Length:
127
Species:
Homo sapiens
Mutation(s):
R104H
E.C. Number:
UniProt ID:
P02766
Keyword(s):
Transthyretin
Structure Information
PDB ID:
1X7T
Amyloid Category:
Non-amyloid
Type:
Protein
Global Stoichiometry:
Homo 4-mer - A4
PDB Classification:
TRANSPORT PROTEIN
Method:
X-RAY DIFFRACTION
Resolution (
Å
):
1.6
R free:
0.252
Entry:S-0073
PDB ID: 1XQ8
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Sequence & Sec. Str.
Chain 1
1
M
D
V
F
M
K
G
L
S
K
A
K
E
G
V
V
A
A
A
E
K
T
K
Q
G
25
26
V
A
E
A
A
G
K
T
K
E
G
V
L
Y
V
G
S
K
T
K
E
G
V
V
H
50
51
G
V
A
T
V
A
E
K
T
K
E
Q
V
T
N
V
G
G
A
V
V
T
G
V
T
75
76
A
V
A
Q
K
T
V
E
G
A
G
S
I
A
A
A
T
G
F
V
K
K
D
Q
L
100
101
G
K
N
E
E
G
A
P
Q
E
G
I
L
E
D
M
P
V
D
P
D
N
E
A
Y
125
126
E
M
P
S
E
E
G
Y
Q
D
Y
E
P
E
A
140
Helix: Magenta; Strand: Yellow; Coil & Turn: White.
Charged residues and Proline are highlighed in blue.
Description
Human micelle-bound alpha-synuclein
Here, the structure and dynamics of micelle-bound Alpha-synuclein (aS) is reported. Val3-Val37 and Lys45-Thr92 form curved Alpha-helices, connected by a well ordered, extended linker in an unexpected anti-parallel arrangement, followed by another short extended region (Gly93-Lys97), overlapping the recently identified chaperone-mediated autophagy recognition motif and a highly mobile tail (Asp98-Ala140). Helix curvature is significantly less than predicted based on the native micelle shape, indicating a deformation of the micelle by aS. Structural and dynamic parameters show a reduced helical content for Ala30-Val37.
Literature
PMID:
15615727
Author(s):
Ulmer, T.S., Bax, A., Cole, N.B., Nussbaum, R.L.
Reference:
J Biol Chem. 2005 Mar 11;280(10):9595-603. Epub 2004 Dec 22
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Protein Information
Protein Name:
Alpha-synuclein
Alternative Name:
Non-A beta component of AD amyloid, Non-A4 component of amyloid precursor
Gene Name:
SNCA, NACP, PARK1
Sequence Length:
140
Species:
Homo sapiens
Mutation(s):
No
E.C. Number:
UniProt ID:
P37840
Keyword(s):
Alpha-synuclein
Structure Information
PDB ID:
1XQ8
Amyloid Category:
Amyloid
Type:
Protein complex
Global Stoichiometry:
Monomer - A
PDB Classification:
LIPID BINDING PROTEIN
Method:
SOLUTION NMR
Resolution (
Å
):
R free:
Entry:S-0074
PDB ID: 1Y1D
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Protein Contacts Atlas
Sequence & Sec. Str.
Chain 1
1
G
P
T
G
T
G
E
S
K
C
P
L
M
V
K
V
L
D
A
V
R
G
S
P
A
25
26
I
N
V
A
V
H
V
F
R
K
A
A
D
D
T
W
E
P
F
A
S
G
K
T
S
50
51
E
S
G
E
L
H
G
L
T
T
E
E
E
F
V
E
G
I
Y
K
V
E
I
D
T
75
76
K
S
Y
W
K
A
L
G
I
S
P
F
H
E
H
A
E
V
V
F
T
A
N
D
S
100
101
G
P
R
R
Y
T
I
A
A
L
L
S
P
Y
S
Y
S
T
T
A
V
V
T
N
P
125
126
K
E
127
Chain 2
1
G
P
T
G
T
G
E
S
K
C
P
L
M
V
K
V
L
D
A
V
R
G
S
P
A
25
26
I
N
V
A
V
H
V
F
R
K
A
A
D
D
T
W
E
P
F
A
S
G
K
T
S
50
51
E
S
G
E
L
H
G
L
T
T
E
E
E
F
V
E
G
I
Y
K
V
E
I
D
T
75
76
K
S
Y
W
K
A
L
G
I
S
P
F
H
E
H
A
E
V
V
F
T
A
N
D
S
100
101
G
P
R
R
Y
T
I
A
A
L
L
S
P
Y
S
Y
S
T
T
A
V
V
T
N
P
125
126
K
E
127
Helix: Magenta; Strand: Yellow; Coil & Turn: White.
Charged residues and Proline are highlighed in blue.
Description
Human transthyretin in complex with iododiflunisal
Ex vivo and in vitro studies have revealed the remarkable amyloid inhibitory potency and specificity of iododiflunisal in relation to transthyretin. the crystal structure of transthyretin complexed with this diflunisal derivative is reported, which enables a detailed analysis of the protein-ligand interactions. Iododiflunisal binds very deep in the hormone-binding channel. The iodine substituent is tightly anchored into a pocket of the binding site and the fluorine atoms provide extra hydrophobic contacts with the protein. The carboxylate substituent is involved in an electrostatic interaction with the N(zeta) of a lysine residue. Moreover, ligand-induced conformational alterations in the side chain of some residues result in the formation of new intersubunit hydrogen bonds. All these new interactions, induced by iododiflunisal, increase the stability of the tetramer impairing the formation of amyloid fibrils.
Literature
PMID:
15689188
Author(s):
Gales, L., Macedo-Ribeiro, S., Arsequell, G., Valencia, G., Saraiva, M.J., Damas, A.M.
Reference:
Biochem J. 2005 Jun 1;388(Pt 2):615-21
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Protein Information
Protein Name:
Transthyretin
Alternative Name:
ATTR, Prealbumin, TBPA
Gene Name:
TTR, PALB
Sequence Length:
127
Species:
Homo sapiens
Mutation(s):
No
E.C. Number:
UniProt ID:
P02766
Keyword(s):
Transthyretin
Structure Information
PDB ID:
1Y1D
Amyloid Category:
Non-amyloid
Type:
Inhibitor complex
Global Stoichiometry:
Homo 4-mer - A4
PDB Classification:
TRANSPORT PROTEIN
Method:
X-RAY DIFFRACTION
Resolution (
Å
):
1.7
R free:
0.222
Ligand Information
Ligand ID
Chain ID
Ligand Formula
Ligand MW
Ligand Name
Ligand SMILES
InChI Key
FHI
A
C13 H7 F2 I O3
376.09
2',4'-DIFLUORO-4-HYDROXY-5-IODO-1,1'-BIPHENYL-3-CARBOXYLIC ACID
c1cc(c(cc1F)F)c2cc(c(c(c2)I)O)C(=O)O
SSYOLLIRAAWGDJ-UHFFFAOYSA-N
FHI
B
C13 H7 F2 I O3
376.09
2',4'-DIFLUORO-4-HYDROXY-5-IODO-1,1'-BIPHENYL-3-CARBOXYLIC ACID
c1cc(c(cc1F)F)c2cc(c(c(c2)I)O)C(=O)O
SSYOLLIRAAWGDJ-UHFFFAOYSA-N
Entry:S-0075
PDB ID: 1YJO
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Sequence & Sec. Str.
Chain 1
1
N
N
Q
Q
N
Y
6
Helix: Magenta; Strand: Yellow; Coil & Turn: White.
Charged residues and Proline are highlighed in blue.
Description
Structure of NNQQNY from yeast prion Sup35 with zinc acetate; Structure of the cross-beta spine
For the yeast protein Sup35, conversion to amyloid-like fibrils is associated with a transmissible infection akin to that caused by mammalian prions. A seven-residue peptide segment from Sup35 forms amyloid-like fibrils and closely related microcrystals, from which the atomic structure of the cross-Beta spine is determined. It is a double Beta-sheet, with each sheet formed from parallel segments stacked in register. Side chains protruding from the two sheets form a dry, tightly self-complementing steric zipper, bonding the sheets. Within each sheet, every segment is bound to its two neighbouring segments through stacks of both backbone and side-chain hydrogen bonds. The structure illuminates the stability of amyloid fibrils, their self-seeding characteristic and their tendency to form polymorphic structures.
Literature
PMID:
15944695
Author(s):
Nelson, R., Sawaya, M.R., Balbirnie, M., Madsen, A.O., Riekel, C., Grothe, R., Eisenberg, D.
Reference:
Nature. 2005 Jun 9;435(7043):773-8
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Protein Information
Protein Name:
Eukaryotic peptide chain release factor GTP-binding subunit
Alternative Name:
Gene Name:
Sequence Length:
6
Species:
Saccharomyces cerevisiae
Mutation(s):
No
E.C. Number:
UniProt ID:
P05453
Keyword(s):
Eukaryotic peptide chain release factor GTP-binding subunit
Structure Information
PDB ID:
1YJO
Amyloid Category:
Amyloid
Type:
Fibril
Global Stoichiometry:
Homo 2-mer - A2
PDB Classification:
PROTEIN BINDING
Method:
X-RAY DIFFRACTION
Resolution (
Å
):
1.3
R free:
0.152
Ligand Information
Ligand ID
Chain ID
Ligand Formula
Ligand MW
Ligand Name
Ligand SMILES
InChI Key
ACY
A
C2 H4 O2
60.05
ACETIC ACID
CC(=O)O
QTBSBXVTEAMEQO-UHFFFAOYSA-N
ZN
A
Zn 2
65.41
ZINC ION
[Zn+2]
PTFCDOFLOPIGGS-UHFFFAOYSA-N
Entry:S-0076
PDB ID: 1YJP
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Sequence & Sec. Str.
Chain 1
1
G
N
N
Q
Q
N
Y
7
Helix: Magenta; Strand: Yellow; Coil & Turn: White.
Charged residues and Proline are highlighed in blue.
Description
Structure of GNNQQNY from yeast prion Sup35; Structure of the cross-beta spine
For the yeast protein Sup35, conversion to amyloid-like fibrils is associated with a transmissible infection akin to that caused by mammalian prions. A seven-residue peptide segment from Sup35 forms amyloid-like fibrils and closely related microcrystals, from which the atomic structure of the cross-Beta spine is determined. It is a double Beta-sheet, with each sheet formed from parallel segments stacked in register. Side chains protruding from the two sheets form a dry, tightly self-complementing steric zipper, bonding the sheets. Within each sheet, every segment is bound to its two neighbouring segments through stacks of both backbone and side-chain hydrogen bonds. The structure illuminates the stability of amyloid fibrils, their self-seeding characteristic and their tendency to form polymorphic structures.
Literature
PMID:
15944695
Author(s):
Nelson, R., Sawaya, M.R., Balbirnie, M., Madsen, A.O., Riekel, C., Grothe, R., Eisenberg, D.
Reference:
Nature. 2005 Jun 9;435(7043):773-8
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Entry:
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Structure:
PDB
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Contact Network:
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Protein Information
Protein Name:
Eukaryotic peptide chain release factor GTP-binding subunit
Alternative Name:
Gene Name:
Sequence Length:
7
Species:
Saccharomyces cerevisiae
Mutation(s):
No
E.C. Number:
UniProt ID:
P05453
Keyword(s):
Eukaryotic peptide chain release factor GTP-binding subunit
Structure Information
PDB ID:
1YJP
Amyloid Category:
Amyloid
Type:
Fibril
Global Stoichiometry:
Homo 2-mer - A2
PDB Classification:
PROTEIN BINDING
Method:
X-RAY DIFFRACTION
Resolution (
Å
):
1.8
R free:
0.19
Entry:S-0077
PDB ID: 1Z0Q
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Sequence & Sec. Str.
Chain 1
1
D
A
E
F
R
H
D
S
G
Y
E
V
H
H
Q
K
L
V
F
F
A
E
D
V
G
25
26
S
N
K
G
A
I
I
G
L
M
V
G
G
V
V
I
A
42
Helix: Magenta; Strand: Yellow; Coil & Turn: White.
Charged residues and Proline are highlighed in blue.
Description
Aqueous Solution Structure of the Alzheimer's Disease Abeta Peptide (1-42)
The conformational path that can lead the ABeta-(1-42) peptide from the native state is experimentally investigated, which is represented by an Alpha helix embedded in the membrane, to the final state in the amyloid fibrils, which is characterized by Beta-sheet structures. The NMR structure solved in HFIP/H2O with high water content showed that, on going from very apolar to polar environments, the long N-terminal helix is essentially retained, whereas the shorter C-terminal helix is lost.
Literature
PMID:
16444756
Author(s):
Tomaselli, S., Esposito, V., Vangone, P., van Nuland, N.A., Bonvin, A.M., Guerrini, R., Tancredi, T., Temussi, P.A., Picone, D.
Reference:
Chembiochem. 2006 Feb;7(2):257-67
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Protein Information
Protein Name:
Amyloid-beta A4 protein
Alternative Name:
ABPP, APPI, Alzheimer disease amyloid protein, Amyloid precursor protein, Amyloid-beta precursor protein, Cerebral vascular amyloid peptide, PreA4, Protease nexin-II
Gene Name:
APP, A4, AD1
Sequence Length:
42
Species:
Homo sapiens
Mutation(s):
No
E.C. Number:
UniProt ID:
P05067
Keyword(s):
Alzheimer's disease amyloid
Structure Information
PDB ID:
1Z0Q
Amyloid Category:
Amyloid
Type:
Peptide
Global Stoichiometry:
Monomer - A
PDB Classification:
PROTEIN BINDING
Method:
SOLUTION NMR
Resolution (
Å
):
R free:
Entry:S-0078
PDB ID: 1ZE7
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Sequence & Sec. Str.
Chain 1
1
X
D
A
E
F
R
H
D
S
G
Y
E
V
H
H
Q
K
X
18
Helix: Magenta; Strand: Yellow; Coil & Turn: White.
Charged residues and Proline are highlighed in blue.
Description
Structural changes of region 1-16 of the Alzheimer disease amyloid beta-peptide upon zinc binding and in vitro aging; in water solution at pH 6.5
the solution structure of the ABeta-(1-16)-Zn(2+) complex in aqueous solution at pH 6.5. The residues His(6), His(13), and His(14) and the Glu(11) carboxylate were identified as ligands that tetrahedrally coordinate the Zn(II) cation. In vitro aging experiments on ABeta-(1-16) led to the formation of truncated and isomerized species. The major isomer generated, ABeta-(1-16)-l-iso-Asp(7), displayed a local conformational change in the His(6)-Ser(8) region but kept a zinc binding propensity via a coordination mode involving l-iso-Asp(7). These results shows the potentiality of the region 1-16 of ABeta to be used as a therapeutic target. The absence of oligomerization upon zinc binding has also been shown.
Literature
PMID:
16301322
Author(s):
Zirah, S., Kozin, S.A., Mazur, A.K., Blond, A., Cheminant, M., Segalas-Milazzo, I., Debey, P., Rebuffat, S.
Reference:
J Biol Chem. 2006 Jan 27;281(4):2151-61. Epub 2005 Nov 21
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Structure:
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Protein Information
Protein Name:
Amyloid-beta A4 protein
Alternative Name:
Gene Name:
Sequence Length:
18
Species:
Homo sapiens
Mutation(s):
No
E.C. Number:
UniProt ID:
P05067
Keyword(s):
16-mer from Alzheimer's disease amyloid Protein
Structure Information
PDB ID:
1ZE7
Amyloid Category:
Non-amyloid
Type:
Inhibitor complex
Global Stoichiometry:
PDB Classification:
METAL BINDING PROTEIN
Method:
SOLUTION NMR
Resolution (
Å
):
R free:
Ligand Information
Ligand ID
Chain ID
Ligand Formula
Ligand MW
Ligand Name
Ligand SMILES
InChI Key
ACE
A
C2 H4 O
44.05
ACETYL GROUP
CC=O
IKHGUXGNUITLKF-UHFFFAOYSA-N
NH2
A
H2 N
16.02
AMINO GROUP
[NH2]
QGZKDVFQNNGYKY-UHFFFAOYAF
Entry:S-0079
PDB ID: 1ZE9
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Sequence & Sec. Str.
Chain 1
1
X
D
A
E
F
R
H
D
S
G
Y
E
V
H
H
Q
K
X
18
Helix: Magenta; Strand: Yellow; Coil & Turn: White.
Charged residues and Proline are highlighed in blue.
Description
Zinc-binding domain of Alzheimer's disease amyloid beta-peptide complexed with a zinc (II) cation
the solution structure of the ABeta-(1-16)-Zn(2+) complex in aqueous solution at pH 6.5. The residues His(6), His(13), and His(14) and the Glu(11) carboxylate were identified as ligands that tetrahedrally coordinate the Zn(II) cation. In vitro aging experiments on ABeta-(1-16) led to the formation of truncated and isomerized species. The major isomer generated, ABeta-(1-16)-l-iso-Asp(7), displayed a local conformational change in the His(6)-Ser(8) region but kept a zinc binding propensity via a coordination mode involving l-iso-Asp(7). These results shows the potentiality of the region 1-16 of ABeta to be used as a therapeutic target. The absence of oligomerization upon zinc binding has also been shown.
Literature
PMID:
16301322
Author(s):
Zirah, S., Kozin, S.A., Mazur, A.K., Blond, A., Cheminant, M., Segalas-Milazzo, I., Debey, P., Rebuffat, S.
Reference:
J Biol Chem. 2006 Jan 27;281(4):2151-61. Epub 2005 Nov 21
Download
Entry:
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Structure:
PDB
CIF
FASTA
Contact Network:
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Protein Information
Protein Name:
Amyloid-beta A4 protein
Alternative Name:
Gene Name:
Sequence Length:
18
Species:
Homo sapiens
Mutation(s):
No
E.C. Number:
UniProt ID:
P05067
Keyword(s):
16-mer from Alzheimer's disease amyloid Protein
Structure Information
PDB ID:
1ZE9
Amyloid Category:
Non-amyloid
Type:
Inhibitor complex
Global Stoichiometry:
PDB Classification:
METAL BINDING PROTEIN
Method:
SOLUTION NMR
Resolution (
Å
):
R free:
Ligand Information
Ligand ID
Chain ID
Ligand Formula
Ligand MW
Ligand Name
Ligand SMILES
InChI Key
ACE
A
C2 H4 O
44.05
ACETYL GROUP
CC=O
IKHGUXGNUITLKF-UHFFFAOYSA-N
NH2
A
H2 N
16.02
AMINO GROUP
[NH2]
QGZKDVFQNNGYKY-UHFFFAOYAF
ZN
A
Zn 2
65.41
ZINC ION
[Zn+2]
PTFCDOFLOPIGGS-UHFFFAOYSA-N
Entry:S-0080
PDB ID: 2A3W
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Protein Contacts Atlas
Sequence & Sec. Str.
Chain 1
1
H
T
D
L
S
G
K
V
F
V
F
P
R
E
S
V
T
D
H
V
N
L
I
T
P
25
26
L
E
K
P
L
Q
N
F
T
L
C
F
R
A
Y
S
D
L
S
R
A
Y
S
L
F
50
51
S
Y
N
T
Q
G
R
D
N
E
L
L
V
Y
K
E
R
V
G
E
Y
S
L
Y
I
75
76
G
R
H
K
V
T
S
K
V
I
E
K
F
P
A
P
V
H
I
C
V
S
W
E
S
100
101
S
S
G
I
A
E
F
W
I
N
G
T
P
L
V
K
K
G
L
R
Q
G
Y
F
V
125
126
E
A
Q
P
K
I
V
L
G
Q
E
Q
D
S
Y
G
G
K
F
D
R
S
Q
S
F
150
151
V
G
E
I
G
D
L
Y
M
W
D
S
V
L
P
P
E
N
I
L
S
A
Y
Q
G
175
176
T
P
L
P
A
N
I
L
D
W
Q
A
L
N
Y
E
I
R
G
Y
V
I
I
K
P
200
201
L
V
W
V
204
Chain 2
1
H
T
D
L
S
G
K
V
F
V
F
P
R
E
S
V
T
D
H
V
N
L
I
T
P
25
26
L
E
K
P
L
Q
N
F
T
L
C
F
R
A
Y
S
D
L
S
R
A
Y
S
L
F
50
51
S
Y
N
T
Q
G
R
D
N
E
L
L
V
Y
K
E
R
V
G
E
Y
S
L
Y
I
75
76
G
R
H
K
V
T
S
K
V
I
E
K
F
P
A
P
V
H
I
C
V
S
W
E
S
100
101
S
S
G
I
A
E
F
W
I
N
G
T
P
L
V
K
K
G
L
R
Q
G
Y
F
V
125
126
E
A
Q
P
K
I
V
L
G
Q
E
Q
D
S
Y
G
G
K
F
D
R
S
Q
S
F
150
151
V
G
E
I
G
D
L
Y
M
W
D
S
V
L
P
P
E
N
I
L
S
A
Y
Q
G
175
176
T
P
L
P
A
N
I
L
D
W
Q
A
L
N
Y
E
I
R
G
Y
V
I
I
K
P
200
201
L
V
W
V
204
Chain 3
1
H
T
D
L
S
G
K
V
F
V
F
P
R
E
S
V
T
D
H
V
N
L
I
T
P
25
26
L
E
K
P
L
Q
N
F
T
L
C
F
R
A
Y
S
D
L
S
R
A
Y
S
L
F
50
51
S
Y
N
T
Q
G
R
D
N
E
L
L
V
Y
K
E
R
V
G
E
Y
S
L
Y
I
75
76
G
R
H
K
V
T
S
K
V
I
E
K
F
P
A
P
V
H
I
C
V
S
W
E
S
100
101
S
S
G
I
A
E
F
W
I
N
G
T
P
L
V
K
K
G
L
R
Q
G
Y
F
V
125
126
E
A
Q
P
K
I
V
L
G
Q
E
Q
D
S
Y
G
G
K
F
D
R
S
Q
S
F
150
151
V
G
E
I
G
D
L
Y
M
W
D
S
V
L
P
P
E
N
I
L
S
A
Y
Q
G
175
176
T
P
L
P
A
N
I
L
D
W
Q
A
L
N
Y
E
I
R
G
Y
V
I
I
K
P
200
201
L
V
W
V
204
Chain 4
1
H
T
D
L
S
G
K
V
F
V
F
P
R
E
S
V
T
D
H
V
N
L
I
T
P
25
26
L
E
K
P
L
Q
N
F
T
L
C
F
R
A
Y
S
D
L
S
R
A
Y
S
L
F
50
51
S
Y
N
T
Q
G
R
D
N
E
L
L
V
Y
K
E
R
V
G
E
Y
S
L
Y
I
75
76
G
R
H
K
V
T
S
K
V
I
E
K
F
P
A
P
V
H
I
C
V
S
W
E
S
100
101
S
S
G
I
A
E
F
W
I
N
G
T
P
L
V
K
K
G
L
R
Q
G
Y
F
V
125
126
E
A
Q
P
K
I
V
L
G
Q
E
Q
D
S
Y
G
G
K
F
D
R
S
Q
S
F
150
151
V
G
E
I
G
D
L
Y
M
W
D
S
V
L
P
P
E
N
I
L
S
A
Y
Q
G
175
176
T
P
L
P
A
N
I
L
D
W
Q
A
L
N
Y
E
I
R
G
Y
V
I
I
K
P
200
201
L
V
W
V
204
Chain 5
1
H
T
D
L
S
G
K
V
F
V
F
P
R
E
S
V
T
D
H
V
N
L
I
T
P
25
26
L
E
K
P
L
Q
N
F
T
L
C
F
R
A
Y
S
D
L
S
R
A
Y
S
L
F
50
51
S
Y
N
T
Q
G
R
D
N
E
L
L
V
Y
K
E
R
V
G
E
Y
S
L
Y
I
75
76
G
R
H
K
V
T
S
K
V
I
E
K
F
P
A
P
V
H
I
C
V
S
W
E
S
100
101
S
S
G
I
A
E
F
W
I
N
G
T
P
L
V
K
K
G
L
R
Q
G
Y
F
V
125
126
E
A
Q
P
K
I
V
L
G
Q
E
Q
D
S
Y
G
G
K
F
D
R
S
Q
S
F
150
151
V
G
E
I
G
D
L
Y
M
W
D
S
V
L
P
P
E
N
I
L
S
A
Y
Q
G
175
176
T
P
L
P
A
N
I
L
D
W
Q
A
L
N
Y
E
I
R
G
Y
V
I
I
K
P
200
201
L
V
W
V
204
Chain 6
1
H
T
D
L
S
G
K
V
F
V
F
P
R
E
S
V
T
D
H
V
N
L
I
T
P
25
26
L
E
K
P
L
Q
N
F
T
L
C
F
R
A
Y
S
D
L
S
R
A
Y
S
L
F
50
51
S
Y
N
T
Q
G
R
D
N
E
L
L
V
Y
K
E
R
V
G
E
Y
S
L
Y
I
75
76
G
R
H
K
V
T
S
K
V
I
E
K
F
P
A
P
V
H
I
C
V
S
W
E
S
100
101
S
S
G
I
A
E
F
W
I
N
G
T
P
L
V
K
K
G
L
R
Q
G
Y
F
V
125
126
E
A
Q
P
K
I
V
L
G
Q
E
Q
D
S
Y
G
G
K
F
D
R
S
Q
S
F
150
151
V
G
E
I
G
D
L
Y
M
W
D
S
V
L
P
P
E
N
I
L
S
A
Y
Q
G
175
176
T
P
L
P
A
N
I
L
D
W
Q
A
L
N
Y
E
I
R
G
Y
V
I
I
K
P
200
201
L
V
W
V
204
Chain 7
1
H
T
D
L
S
G
K
V
F
V
F
P
R
E
S
V
T
D
H
V
N
L
I
T
P
25
26
L
E
K
P
L
Q
N
F
T
L
C
F
R
A
Y
S
D
L
S
R
A
Y
S
L
F
50
51
S
Y
N
T
Q
G
R
D
N
E
L
L
V
Y
K
E
R
V
G
E
Y
S
L
Y
I
75
76
G
R
H
K
V
T
S
K
V
I
E
K
F
P
A
P
V
H
I
C
V
S
W
E
S
100
101
S
S
G
I
A
E
F
W
I
N
G
T
P
L
V
K
K
G
L
R
Q
G
Y
F
V
125
126
E
A
Q
P
K
I
V
L
G
Q
E
Q
D
S
Y
G
G
K
F
D
R
S
Q
S
F
150
151
V
G
E
I
G
D
L
Y
M
W
D
S
V
L
P
P
E
N
I
L
S
A
Y
Q
G
175
176
T
P
L
P
A
N
I
L
D
W
Q
A
L
N
Y
E
I
R
G
Y
V
I
I
K
P
200
201
L
V
W
V
204
Chain 8
1
H
T
D
L
S
G
K
V
F
V
F
P
R
E
S
V
T
D
H
V
N
L
I
T
P
25
26
L
E
K
P
L
Q
N
F
T
L
C
F
R
A
Y
S
D
L
S
R
A
Y
S
L
F
50
51
S
Y
N
T
Q
G
R
D
N
E
L
L
V
Y
K
E
R
V
G
E
Y
S
L
Y
I
75
76
G
R
H
K
V
T
S
K
V
I
E
K
F
P
A
P
V
H
I
C
V
S
W
E
S
100
101
S
S
G
I
A
E
F
W
I
N
G
T
P
L
V
K
K
G
L
R
Q
G
Y
F
V
125
126
E
A
Q
P
K
I
V
L
G
Q
E
Q
D
S
Y
G
G
K
F
D
R
S
Q
S
F
150
151
V
G
E
I
G
D
L
Y
M
W
D
S
V
L
P
P
E
N
I
L
S
A
Y
Q
G
175
176
T
P
L
P
A
N
I
L
D
W
Q
A
L
N
Y
E
I
R
G
Y
V
I
I
K
P
200
201
L
V
W
V
204
Chain 9
1
H
T
D
L
S
G
K
V
F
V
F
P
R
E
S
V
T
D
H
V
N
L
I
T
P
25
26
L
E
K
P
L
Q
N
F
T
L
C
F
R
A
Y
S
D
L
S
R
A
Y
S
L
F
50
51
S
Y
N
T
Q
G
R
D
N
E
L
L
V
Y
K
E
R
V
G
E
Y
S
L
Y
I
75
76
G
R
H
K
V
T
S
K
V
I
E
K
F
P
A
P
V
H
I
C
V
S
W
E
S
100
101
S
S
G
I
A
E
F
W
I
N
G
T
P
L
V
K
K
G
L
R
Q
G
Y
F
V
125
126
E
A
Q
P
K
I
V
L
G
Q
E
Q
D
S
Y
G
G
K
F
D
R
S
Q
S
F
150
151
V
G
E
I
G
D
L
Y
M
W
D
S
V
L
P
P
E
N
I
L
S
A
Y
Q
G
175
176
T
P
L
P
A
N
I
L
D
W
Q
A
L
N
Y
E
I
R
G
Y
V
I
I
K
P
200
201
L
V
W
V
204
Chain 10
1
H
T
D
L
S
G
K
V
F
V
F
P
R
E
S
V
T
D
H
V
N
L
I
T
P
25
26
L
E
K
P
L
Q
N
F
T
L
C
F
R
A
Y
S
D
L
S
R
A
Y
S
L
F
50
51
S
Y
N
T
Q
G
R
D
N
E
L
L
V
Y
K
E
R
V
G
E
Y
S
L
Y
I
75
76
G
R
H
K
V
T
S
K
V
I
E
K
F
P
A
P
V
H
I
C
V
S
W
E
S
100
101
S
S
G
I
A
E
F
W
I
N
G
T
P
L
V
K
K
G
L
R
Q
G
Y
F
V
125
126
E
A
Q
P
K
I
V
L
G
Q
E
Q
D
S
Y
G
G
K
F
D
R
S
Q
S
F
150
151
V
G
E
I
G
D
L
Y
M
W
D
S
V
L
P
P
E
N
I
L
S
A
Y
Q
G
175
176
T
P
L
P
A
N
I
L
D
W
Q
A
L
N
Y
E
I
R
G
Y
V
I
I
K
P
200
201
L
V
W
V
204
Chain 11
1
H
T
D
L
S
G
K
V
F
V
F
P
R
E
S
V
T
D
H
V
N
L
I
T
P
25
26
L
E
K
P
L
Q
N
F
T
L
C
F
R
A
Y
S
D
L
S
R
A
Y
S
L
F
50
51
S
Y
N
T
Q
G
R
D
N
E
L
L
V
Y
K
E
R
V
G
E
Y
S
L
Y
I
75
76
G
R
H
K
V
T
S
K
V
I
E
K
F
P
A
P
V
H
I
C
V
S
W
E
S
100
101
S
S
G
I
A
E
F
W
I
N
G
T
P
L
V
K
K
G
L
R
Q
G
Y
F
V
125
126
E
A
Q
P
K
I
V
L
G
Q
E
Q
D
S
Y
G
G
K
F
D
R
S
Q
S
F
150
151
V
G
E
I
G
D
L
Y
M
W
D
S
V
L
P
P
E
N
I
L
S
A
Y
Q
G
175
176
T
P
L
P
A
N
I
L
D
W
Q
A
L
N
Y
E
I
R
G
Y
V
I
I
K
P
200
201
L
V
W
V
204
Chain 12
1
H
T
D
L
S
G
K
V
F
V
F
P
R
E
S
V
T
D
H
V
N
L
I
T
P
25
26
L
E
K
P
L
Q
N
F
T
L
C
F
R
A
Y
S
D
L
S
R
A
Y
S
L
F
50
51
S
Y
N
T
Q
G
R
D
N
E
L
L
V
Y
K
E
R
V
G
E
Y
S
L
Y
I
75
76
G
R
H
K
V
T
S
K
V
I
E
K
F
P
A
P
V
H
I
C
V
S
W
E
S
100
101
S
S
G
I
A
E
F
W
I
N
G
T
P
L
V
K
K
G
L
R
Q
G
Y
F
V
125
126
E
A
Q
P
K
I
V
L
G
Q
E
Q
D
S
Y
G
G
K
F
D
R
S
Q
S
F
150
151
V
G
E
I
G
D
L
Y
M
W
D
S
V
L
P
P
E
N
I
L
S
A
Y
Q
G
175
176
T
P
L
P
A
N
I
L
D
W
Q
A
L
N
Y
E
I
R
G
Y
V
I
I
K
P
200
201
L
V
W
V
204
Chain 13
1
H
T
D
L
S
G
K
V
F
V
F
P
R
E
S
V
T
D
H
V
N
L
I
T
P
25
26
L
E
K
P
L
Q
N
F
T
L
C
F
R
A
Y
S
D
L
S
R
A
Y
S
L
F
50
51
S
Y
N
T
Q
G
R
D
N
E
L
L
V
Y
K
E
R
V
G
E
Y
S
L
Y
I
75
76
G
R
H
K
V
T
S
K
V
I
E
K
F
P
A
P
V
H
I
C
V
S
W
E
S
100
101
S
S
G
I
A
E
F
W
I
N
G
T
P
L
V
K
K
G
L
R
Q
G
Y
F
V
125
126
E
A
Q
P
K
I
V
L
G
Q
E
Q
D
S
Y
G
G
K
F
D
R
S
Q
S
F
150
151
V
G
E
I
G
D
L
Y
M
W
D
S
V
L
P
P
E
N
I
L
S
A
Y
Q
G
175
176
T
P
L
P
A
N
I
L
D
W
Q
A
L
N
Y
E
I
R
G
Y
V
I
I
K
P
200
201
L
V
W
V
204
Chain 14
1
H
T
D
L
S
G
K
V
F
V
F
P
R
E
S
V
T
D
H
V
N
L
I
T
P
25
26
L
E
K
P
L
Q
N
F
T
L
C
F
R
A
Y
S
D
L
S
R
A
Y
S
L
F
50
51
S
Y
N
T
Q
G
R
D
N
E
L
L
V
Y
K
E
R
V
G
E
Y
S
L
Y
I
75
76
G
R
H
K
V
T
S
K
V
I
E
K
F
P
A
P
V
H
I
C
V
S
W
E
S
100
101
S
S
G
I
A
E
F
W
I
N
G
T
P
L
V
K
K
G
L
R
Q
G
Y
F
V
125
126
E
A
Q
P
K
I
V
L
G
Q
E
Q
D
S
Y
G
G
K
F
D
R
S
Q
S
F
150
151
V
G
E
I
G
D
L
Y
M
W
D
S
V
L
P
P
E
N
I
L
S
A
Y
Q
G
175
176
T
P
L
P
A
N
I
L
D
W
Q
A
L
N
Y
E
I
R
G
Y
V
I
I
K
P
200
201
L
V
W
V
204
Chain 15
1
H
T
D
L
S
G
K
V
F
V
F
P
R
E
S
V
T
D
H
V
N
L
I
T
P
25
26
L
E
K
P
L
Q
N
F
T
L
C
F
R
A
Y
S
D
L
S
R
A
Y
S
L
F
50
51
S
Y
N
T
Q
G
R
D
N
E
L
L
V
Y
K
E
R
V
G
E
Y
S
L
Y
I
75
76
G
R
H
K
V
T
S
K
V
I
E
K
F
P
A
P
V
H
I
C
V
S
W
E
S
100
101
S
S
G
I
A
E
F
W
I
N
G
T
P
L
V
K
K
G
L
R
Q
G
Y
F
V
125
126
E
A
Q
P
K
I
V
L
G
Q
E
Q
D
S
Y
G
G
K
F
D
R
S
Q
S
F
150
151
V
G
E
I
G
D
L
Y
M
W
D
S
V
L
P
P
E
N
I
L
S
A
Y
Q
G
175
176
T
P
L
P
A
N
I
L
D
W
Q
A
L
N
Y
E
I
R
G
Y
V
I
I
K
P
200
201
L
V
W
V
204
Chain 16
1
H
T
D
L
S
G
K
V
F
V
F
P
R
E
S
V
T
D
H
V
N
L
I
T
P
25
26
L
E
K
P
L
Q
N
F
T
L
C
F
R
A
Y
S
D
L
S
R
A
Y
S
L
F
50
51
S
Y
N
T
Q
G
R
D
N
E
L
L
V
Y
K
E
R
V
G
E
Y
S
L
Y
I
75
76
G
R
H
K
V
T
S
K
V
I
E
K
F
P
A
P
V
H
I
C
V
S
W
E
S
100
101
S
S
G
I
A
E
F
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I
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G
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P
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G
L
R
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G
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F
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125
126
E
A
Q
P
K
I
V
L
G
Q
E
Q
D
S
Y
G
G
K
F
D
R
S
Q
S
F
150
151
V
G
E
I
G
D
L
Y
M
W
D
S
V
L
P
P
E
N
I
L
S
A
Y
Q
G
175
176
T
P
L
P
A
N
I
L
D
W
Q
A
L
N
Y
E
I
R
G
Y
V
I
I
K
P
200
201
L
V
W
V
204
Chain 17
1
H
T
D
L
S
G
K
V
F
V
F
P
R
E
S
V
T
D
H
V
N
L
I
T
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25
26
L
E
K
P
L
Q
N
F
T
L
C
F
R
A
Y
S
D
L
S
R
A
Y
S
L
F
50
51
S
Y
N
T
Q
G
R
D
N
E
L
L
V
Y
K
E
R
V
G
E
Y
S
L
Y
I
75
76
G
R
H
K
V
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K
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I
E
K
F
P
A
P
V
H
I
C
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S
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E
S
100
101
S
S
G
I
A
E
F
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I
N
G
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V
K
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G
L
R
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G
Y
F
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125
126
E
A
Q
P
K
I
V
L
G
Q
E
Q
D
S
Y
G
G
K
F
D
R
S
Q
S
F
150
151
V
G
E
I
G
D
L
Y
M
W
D
S
V
L
P
P
E
N
I
L
S
A
Y
Q
G
175
176
T
P
L
P
A
N
I
L
D
W
Q
A
L
N
Y
E
I
R
G
Y
V
I
I
K
P
200
201
L
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W
V
204
Chain 18
1
H
T
D
L
S
G
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F
V
F
P
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E
S
V
T
D
H
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N
L
I
T
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25
26
L
E
K
P
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F
T
L
C
F
R
A
Y
S
D
L
S
R
A
Y
S
L
F
50
51
S
Y
N
T
Q
G
R
D
N
E
L
L
V
Y
K
E
R
V
G
E
Y
S
L
Y
I
75
76
G
R
H
K
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T
S
K
V
I
E
K
F
P
A
P
V
H
I
C
V
S
W
E
S
100
101
S
S
G
I
A
E
F
W
I
N
G
T
P
L
V
K
K
G
L
R
Q
G
Y
F
V
125
126
E
A
Q
P
K
I
V
L
G
Q
E
Q
D
S
Y
G
G
K
F
D
R
S
Q
S
F
150
151
V
G
E
I
G
D
L
Y
M
W
D
S
V
L
P
P
E
N
I
L
S
A
Y
Q
G
175
176
T
P
L
P
A
N
I
L
D
W
Q
A
L
N
Y
E
I
R
G
Y
V
I
I
K
P
200
201
L
V
W
V
204
Chain 19
1
H
T
D
L
S
G
K
V
F
V
F
P
R
E
S
V
T
D
H
V
N
L
I
T
P
25
26
L
E
K
P
L
Q
N
F
T
L
C
F
R
A
Y
S
D
L
S
R
A
Y
S
L
F
50
51
S
Y
N
T
Q
G
R
D
N
E
L
L
V
Y
K
E
R
V
G
E
Y
S
L
Y
I
75
76
G
R
H
K
V
T
S
K
V
I
E
K
F
P
A
P
V
H
I
C
V
S
W
E
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100
101
S
S
G
I
A
E
F
W
I
N
G
T
P
L
V
K
K
G
L
R
Q
G
Y
F
V
125
126
E
A
Q
P
K
I
V
L
G
Q
E
Q
D
S
Y
G
G
K
F
D
R
S
Q
S
F
150
151
V
G
E
I
G
D
L
Y
M
W
D
S
V
L
P
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E
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L
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A
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175
176
T
P
L
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A
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A
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200
201
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204
Chain 20
1
H
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D
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F
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F
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E
S
V
T
D
H
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I
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25
26
L
E
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N
F
T
L
C
F
R
A
Y
S
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A
Y
S
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F
50
51
S
Y
N
T
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D
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E
L
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K
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G
E
Y
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75
76
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101
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Y
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V
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126
E
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Q
P
K
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G
Q
E
Q
D
S
Y
G
G
K
F
D
R
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S
F
150
151
V
G
E
I
G
D
L
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M
W
D
S
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P
P
E
N
I
L
S
A
Y
Q
G
175
176
T
P
L
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Q
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Y
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G
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K
P
200
201
L
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204
Helix: Magenta; Strand: Yellow; Coil & Turn: White.
Charged residues and Proline are highlighed in blue.
Description
Decameric structure of human serum amyloid P-component bound to Bis-1,2-{[(Z)-2-carboxy-2-methyl-1,3-dioxane]-5-yloxycarbamoyl}-ethane
SAP, a protein of the human innate immune system, is universally present in amyloids. Removal of SAP through a specific aggregation mechanism mediated by multivalent ligands appears to provide therapeutic benefit in the progression of this disease. Crystallographic studies reveal that in our novel series of ligands only the methyl and carboxylate moieties of the pyruvate ketal directly interact with the protein, but the geometric constraints imposed by the tether dictate which of two chair conformations are adopted by the pyruvate dioxane ring. Solution studies, as interpreted through a simple thermodynamic model, account for the distribution of pentameric and decameric bound states at different ligand concentrations and indicate that differences in the flexibility of the tether determine the geometry and stability of the specific aggregates formed between SAP and two different bivalent ligands.
Literature
PMID:
16036920
Author(s):
Ho, J.G., Kitov, P.I., Paszkiewicz, E., Sadowska, J., Bundle, D.R., Ng, K.K.
Reference:
J Biol Chem. 2005 Sep 9;280(36):31999-2008. Epub 2005 Jul 20
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Structure:
PDB
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FASTA
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Protein Information
Protein Name:
Serum amyloid P-component
Alternative Name:
9.5S alpha-1-glycoprotein
Gene Name:
APCS, PTX2
Sequence Length:
204
Species:
Homo sapiens
Mutation(s):
No
E.C. Number:
UniProt ID:
P02743
Keyword(s):
Serum amyloid P-component
Structure Information
PDB ID:
2A3W
Amyloid Category:
Non-amyloid
Type:
Aggregating complex
Global Stoichiometry:
Homo 10-mer - A10
PDB Classification:
METAL BINDING PROTEIN
Method:
X-RAY DIFFRACTION
Resolution (
Å
):
2.2
R free:
0.22899999
Ligand Information
Ligand ID
Chain ID
Ligand Formula
Ligand MW
Ligand Name
Ligand SMILES
InChI Key
CA
A
Ca 2
40.08
CALCIUM ION
[Ca+2]
BHPQYMZQTOCNFJ-UHFFFAOYSA-N
CPJ
A
C16 H24 N2 O12
436.37
BIS-1,2-{[(Z)-2-CARBOXY-2-METHYL-1,3-DIOXANE]-5-YLOXYCARBAMOYL}-ETHANE
CC1(OCC(CO1)OC(=O)NCCNC(=O)OC2COC(OC2)(C)C(=O)O)C(=O)O
HAVIIPIIAVTNFO-GXZHHNFCSA-N
CA
B
Ca 2
40.08
CALCIUM ION
[Ca+2]
BHPQYMZQTOCNFJ-UHFFFAOYSA-N
CPJ
B
C16 H24 N2 O12
436.37
BIS-1,2-{[(Z)-2-CARBOXY-2-METHYL-1,3-DIOXANE]-5-YLOXYCARBAMOYL}-ETHANE
CC1(OCC(CO1)OC(=O)NCCNC(=O)OC2COC(OC2)(C)C(=O)O)C(=O)O
HAVIIPIIAVTNFO-GXZHHNFCSA-N
CA
C
Ca 2
40.08
CALCIUM ION
[Ca+2]
BHPQYMZQTOCNFJ-UHFFFAOYSA-N
CPJ
C
C16 H24 N2 O12
436.37
BIS-1,2-{[(Z)-2-CARBOXY-2-METHYL-1,3-DIOXANE]-5-YLOXYCARBAMOYL}-ETHANE
CC1(OCC(CO1)OC(=O)NCCNC(=O)OC2COC(OC2)(C)C(=O)O)C(=O)O
HAVIIPIIAVTNFO-GXZHHNFCSA-N
CA
D
Ca 2
40.08
CALCIUM ION
[Ca+2]
BHPQYMZQTOCNFJ-UHFFFAOYSA-N
CPJ
D
C16 H24 N2 O12
436.37
BIS-1,2-{[(Z)-2-CARBOXY-2-METHYL-1,3-DIOXANE]-5-YLOXYCARBAMOYL}-ETHANE
CC1(OCC(CO1)OC(=O)NCCNC(=O)OC2COC(OC2)(C)C(=O)O)C(=O)O
HAVIIPIIAVTNFO-GXZHHNFCSA-N
CA
E
Ca 2
40.08
CALCIUM ION
[Ca+2]
BHPQYMZQTOCNFJ-UHFFFAOYSA-N
CPJ
E
C16 H24 N2 O12
436.37
BIS-1,2-{[(Z)-2-CARBOXY-2-METHYL-1,3-DIOXANE]-5-YLOXYCARBAMOYL}-ETHANE
CC1(OCC(CO1)OC(=O)NCCNC(=O)OC2COC(OC2)(C)C(=O)O)C(=O)O
HAVIIPIIAVTNFO-GXZHHNFCSA-N
CA
F
Ca 2
40.08
CALCIUM ION
[Ca+2]
BHPQYMZQTOCNFJ-UHFFFAOYSA-N
CA
G
Ca 2
40.08
CALCIUM ION
[Ca+2]
BHPQYMZQTOCNFJ-UHFFFAOYSA-N
CA
H
Ca 2
40.08
CALCIUM ION
[Ca+2]
BHPQYMZQTOCNFJ-UHFFFAOYSA-N
CA
I
Ca 2
40.08
CALCIUM ION
[Ca+2]
BHPQYMZQTOCNFJ-UHFFFAOYSA-N
CA
J
Ca 2
40.08
CALCIUM ION
[Ca+2]
BHPQYMZQTOCNFJ-UHFFFAOYSA-N
CA
K
Ca 2
40.08
CALCIUM ION
[Ca+2]
BHPQYMZQTOCNFJ-UHFFFAOYSA-N
CA
L
Ca 2
40.08
CALCIUM ION
[Ca+2]
BHPQYMZQTOCNFJ-UHFFFAOYSA-N
CPJ
L
C16 H24 N2 O12
436.37
BIS-1,2-{[(Z)-2-CARBOXY-2-METHYL-1,3-DIOXANE]-5-YLOXYCARBAMOYL}-ETHANE
CC1(OCC(CO1)OC(=O)NCCNC(=O)OC2COC(OC2)(C)C(=O)O)C(=O)O
HAVIIPIIAVTNFO-GXZHHNFCSA-N
CA
M
Ca 2
40.08
CALCIUM ION
[Ca+2]
BHPQYMZQTOCNFJ-UHFFFAOYSA-N
CPJ
M
C16 H24 N2 O12
436.37
BIS-1,2-{[(Z)-2-CARBOXY-2-METHYL-1,3-DIOXANE]-5-YLOXYCARBAMOYL}-ETHANE
CC1(OCC(CO1)OC(=O)NCCNC(=O)OC2COC(OC2)(C)C(=O)O)C(=O)O
HAVIIPIIAVTNFO-GXZHHNFCSA-N
CA
N
Ca 2
40.08
CALCIUM ION
[Ca+2]
BHPQYMZQTOCNFJ-UHFFFAOYSA-N
CPJ
N
C16 H24 N2 O12
436.37
BIS-1,2-{[(Z)-2-CARBOXY-2-METHYL-1,3-DIOXANE]-5-YLOXYCARBAMOYL}-ETHANE
CC1(OCC(CO1)OC(=O)NCCNC(=O)OC2COC(OC2)(C)C(=O)O)C(=O)O
HAVIIPIIAVTNFO-GXZHHNFCSA-N
CA
O
Ca 2
40.08
CALCIUM ION
[Ca+2]
BHPQYMZQTOCNFJ-UHFFFAOYSA-N
CA
P
Ca 2
40.08
CALCIUM ION
[Ca+2]
BHPQYMZQTOCNFJ-UHFFFAOYSA-N
CPJ
P
C16 H24 N2 O12
436.37
BIS-1,2-{[(Z)-2-CARBOXY-2-METHYL-1,3-DIOXANE]-5-YLOXYCARBAMOYL}-ETHANE
CC1(OCC(CO1)OC(=O)NCCNC(=O)OC2COC(OC2)(C)C(=O)O)C(=O)O
HAVIIPIIAVTNFO-GXZHHNFCSA-N
CA
Q
Ca 2
40.08
CALCIUM ION
[Ca+2]
BHPQYMZQTOCNFJ-UHFFFAOYSA-N
CPJ
Q
C16 H24 N2 O12
436.37
BIS-1,2-{[(Z)-2-CARBOXY-2-METHYL-1,3-DIOXANE]-5-YLOXYCARBAMOYL}-ETHANE
CC1(OCC(CO1)OC(=O)NCCNC(=O)OC2COC(OC2)(C)C(=O)O)C(=O)O
HAVIIPIIAVTNFO-GXZHHNFCSA-N
CA
R
Ca 2
40.08
CALCIUM ION
[Ca+2]
BHPQYMZQTOCNFJ-UHFFFAOYSA-N
CA
S
Ca 2
40.08
CALCIUM ION
[Ca+2]
BHPQYMZQTOCNFJ-UHFFFAOYSA-N
CA
T
Ca 2
40.08
CALCIUM ION
[Ca+2]
BHPQYMZQTOCNFJ-UHFFFAOYSA-N
Entry:S-0081
PDB ID: 2A3X
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Protein Contacts Atlas
Sequence & Sec. Str.
Chain 1
1
H
T
D
L
S
G
K
V
F
V
F
P
R
E
S
V
T
D
H
V
N
L
I
T
P
25
26
L
E
K
P
L
Q
N
F
T
L
C
F
R
A
Y
S
D
L
S
R
A
Y
S
L
F
50
51
S
Y
N
T
Q
G
R
D
N
E
L
L
V
Y
K
E
R
V
G
E
Y
S
L
Y
I
75
76
G
R
H
K
V
T
S
K
V
I
E
K
F
P
A
P
V
H
I
C
V
S
W
E
S
100
101
S
S
G
I
A
E
F
W
I
N
G
T
P
L
V
K
K
G
L
R
Q
G
Y
F
V
125
126
E
A
Q
P
K
I
V
L
G
Q
E
Q
D
S
Y
G
G
K
F
D
R
S
Q
S
F
150
151
V
G
E
I
G
D
L
Y
M
W
D
S
V
L
P
P
E
N
I
L
S
A
Y
Q
G
175
176
T
P
L
P
A
N
I
L
D
W
Q
A
L
N
Y
E
I
R
G
Y
V
I
I
K
P
200
201
L
V
W
V
204
Chain 2
1
H
T
D
L
S
G
K
V
F
V
F
P
R
E
S
V
T
D
H
V
N
L
I
T
P
25
26
L
E
K
P
L
Q
N
F
T
L
C
F
R
A
Y
S
D
L
S
R
A
Y
S
L
F
50
51
S
Y
N
T
Q
G
R
D
N
E
L
L
V
Y
K
E
R
V
G
E
Y
S
L
Y
I
75
76
G
R
H
K
V
T
S
K
V
I
E
K
F
P
A
P
V
H
I
C
V
S
W
E
S
100
101
S
S
G
I
A
E
F
W
I
N
G
T
P
L
V
K
K
G
L
R
Q
G
Y
F
V
125
126
E
A
Q
P
K
I
V
L
G
Q
E
Q
D
S
Y
G
G
K
F
D
R
S
Q
S
F
150
151
V
G
E
I
G
D
L
Y
M
W
D
S
V
L
P
P
E
N
I
L
S
A
Y
Q
G
175
176
T
P
L
P
A
N
I
L
D
W
Q
A
L
N
Y
E
I
R
G
Y
V
I
I
K
P
200
201
L
V
W
V
204
Chain 3
1
H
T
D
L
S
G
K
V
F
V
F
P
R
E
S
V
T
D
H
V
N
L
I
T
P
25
26
L
E
K
P
L
Q
N
F
T
L
C
F
R
A
Y
S
D
L
S
R
A
Y
S
L
F
50
51
S
Y
N
T
Q
G
R
D
N
E
L
L
V
Y
K
E
R
V
G
E
Y
S
L
Y
I
75
76
G
R
H
K
V
T
S
K
V
I
E
K
F
P
A
P
V
H
I
C
V
S
W
E
S
100
101
S
S
G
I
A
E
F
W
I
N
G
T
P
L
V
K
K
G
L
R
Q
G
Y
F
V
125
126
E
A
Q
P
K
I
V
L
G
Q
E
Q
D
S
Y
G
G
K
F
D
R
S
Q
S
F
150
151
V
G
E
I
G
D
L
Y
M
W
D
S
V
L
P
P
E
N
I
L
S
A
Y
Q
G
175
176
T
P
L
P
A
N
I
L
D
W
Q
A
L
N
Y
E
I
R
G
Y
V
I
I
K
P
200
201
L
V
W
V
204
Chain 4
1
H
T
D
L
S
G
K
V
F
V
F
P
R
E
S
V
T
D
H
V
N
L
I
T
P
25
26
L
E
K
P
L
Q
N
F
T
L
C
F
R
A
Y
S
D
L
S
R
A
Y
S
L
F
50
51
S
Y
N
T
Q
G
R
D
N
E
L
L
V
Y
K
E
R
V
G
E
Y
S
L
Y
I
75
76
G
R
H
K
V
T
S
K
V
I
E
K
F
P
A
P
V
H
I
C
V
S
W
E
S
100
101
S
S
G
I
A
E
F
W
I
N
G
T
P
L
V
K
K
G
L
R
Q
G
Y
F
V
125
126
E
A
Q
P
K
I
V
L
G
Q
E
Q
D
S
Y
G
G
K
F
D
R
S
Q
S
F
150
151
V
G
E
I
G
D
L
Y
M
W
D
S
V
L
P
P
E
N
I
L
S
A
Y
Q
G
175
176
T
P
L
P
A
N
I
L
D
W
Q
A
L
N
Y
E
I
R
G
Y
V
I
I
K
P
200
201
L
V
W
V
204
Chain 5
1
H
T
D
L
S
G
K
V
F
V
F
P
R
E
S
V
T
D
H
V
N
L
I
T
P
25
26
L
E
K
P
L
Q
N
F
T
L
C
F
R
A
Y
S
D
L
S
R
A
Y
S
L
F
50
51
S
Y
N
T
Q
G
R
D
N
E
L
L
V
Y
K
E
R
V
G
E
Y
S
L
Y
I
75
76
G
R
H
K
V
T
S
K
V
I
E
K
F
P
A
P
V
H
I
C
V
S
W
E
S
100
101
S
S
G
I
A
E
F
W
I
N
G
T
P
L
V
K
K
G
L
R
Q
G
Y
F
V
125
126
E
A
Q
P
K
I
V
L
G
Q
E
Q
D
S
Y
G
G
K
F
D
R
S
Q
S
F
150
151
V
G
E
I
G
D
L
Y
M
W
D
S
V
L
P
P
E
N
I
L
S
A
Y
Q
G
175
176
T
P
L
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A
N
I
L
D
W
Q
A
L
N
Y
E
I
R
G
Y
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I
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200
201
L
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W
V
204
Chain 6
1
H
T
D
L
S
G
K
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F
V
F
P
R
E
S
V
T
D
H
V
N
L
I
T
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25
26
L
E
K
P
L
Q
N
F
T
L
C
F
R
A
Y
S
D
L
S
R
A
Y
S
L
F
50
51
S
Y
N
T
Q
G
R
D
N
E
L
L
V
Y
K
E
R
V
G
E
Y
S
L
Y
I
75
76
G
R
H
K
V
T
S
K
V
I
E
K
F
P
A
P
V
H
I
C
V
S
W
E
S
100
101
S
S
G
I
A
E
F
W
I
N
G
T
P
L
V
K
K
G
L
R
Q
G
Y
F
V
125
126
E
A
Q
P
K
I
V
L
G
Q
E
Q
D
S
Y
G
G
K
F
D
R
S
Q
S
F
150
151
V
G
E
I
G
D
L
Y
M
W
D
S
V
L
P
P
E
N
I
L
S
A
Y
Q
G
175
176
T
P
L
P
A
N
I
L
D
W
Q
A
L
N
Y
E
I
R
G
Y
V
I
I
K
P
200
201
L
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W
V
204
Chain 7
1
H
T
D
L
S
G
K
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F
V
F
P
R
E
S
V
T
D
H
V
N
L
I
T
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25
26
L
E
K
P
L
Q
N
F
T
L
C
F
R
A
Y
S
D
L
S
R
A
Y
S
L
F
50
51
S
Y
N
T
Q
G
R
D
N
E
L
L
V
Y
K
E
R
V
G
E
Y
S
L
Y
I
75
76
G
R
H
K
V
T
S
K
V
I
E
K
F
P
A
P
V
H
I
C
V
S
W
E
S
100
101
S
S
G
I
A
E
F
W
I
N
G
T
P
L
V
K
K
G
L
R
Q
G
Y
F
V
125
126
E
A
Q
P
K
I
V
L
G
Q
E
Q
D
S
Y
G
G
K
F
D
R
S
Q
S
F
150
151
V
G
E
I
G
D
L
Y
M
W
D
S
V
L
P
P
E
N
I
L
S
A
Y
Q
G
175
176
T
P
L
P
A
N
I
L
D
W
Q
A
L
N
Y
E
I
R
G
Y
V
I
I
K
P
200
201
L
V
W
V
204
Chain 8
1
H
T
D
L
S
G
K
V
F
V
F
P
R
E
S
V
T
D
H
V
N
L
I
T
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25
26
L
E
K
P
L
Q
N
F
T
L
C
F
R
A
Y
S
D
L
S
R
A
Y
S
L
F
50
51
S
Y
N
T
Q
G
R
D
N
E
L
L
V
Y
K
E
R
V
G
E
Y
S
L
Y
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75
76
G
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H
K
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T
S
K
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I
E
K
F
P
A
P
V
H
I
C
V
S
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E
S
100
101
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S
G
I
A
E
F
W
I
N
G
T
P
L
V
K
K
G
L
R
Q
G
Y
F
V
125
126
E
A
Q
P
K
I
V
L
G
Q
E
Q
D
S
Y
G
G
K
F
D
R
S
Q
S
F
150
151
V
G
E
I
G
D
L
Y
M
W
D
S
V
L
P
P
E
N
I
L
S
A
Y
Q
G
175
176
T
P
L
P
A
N
I
L
D
W
Q
A
L
N
Y
E
I
R
G
Y
V
I
I
K
P
200
201
L
V
W
V
204
Chain 9
1
H
T
D
L
S
G
K
V
F
V
F
P
R
E
S
V
T
D
H
V
N
L
I
T
P
25
26
L
E
K
P
L
Q
N
F
T
L
C
F
R
A
Y
S
D
L
S
R
A
Y
S
L
F
50
51
S
Y
N
T
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G
R
D
N
E
L
L
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Y
K
E
R
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G
E
Y
S
L
Y
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75
76
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R
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A
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101
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E
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I
N
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Y
F
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125
126
E
A
Q
P
K
I
V
L
G
Q
E
Q
D
S
Y
G
G
K
F
D
R
S
Q
S
F
150
151
V
G
E
I
G
D
L
Y
M
W
D
S
V
L
P
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E
N
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204
Chain 10
1
H
T
D
L
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K
V
F
V
F
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E
S
V
T
D
H
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N
L
I
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26
L
E
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P
L
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N
F
T
L
C
F
R
A
Y
S
D
L
S
R
A
Y
S
L
F
50
51
S
Y
N
T
Q
G
R
D
N
E
L
L
V
Y
K
E
R
V
G
E
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Y
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75
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G
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E
K
F
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V
H
I
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100
101
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I
A
E
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I
N
G
T
P
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K
G
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G
Y
F
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125
126
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A
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P
K
I
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G
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E
Q
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S
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G
G
K
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Q
S
F
150
151
V
G
E
I
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D
L
Y
M
W
D
S
V
L
P
P
E
N
I
L
S
A
Y
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175
176
T
P
L
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200
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204
Helix: Magenta; Strand: Yellow; Coil & Turn: White.
Charged residues and Proline are highlighed in blue.
Description
Decameric crystal structure of human serum amyloid P-component bound to Bis-1,2-{[(Z)-2carboxy- 2-methyl-1,3-dioxane]- 5-yloxycarbonyl}-piperazine
SAP, a protein of the human innate immune system, is universally present in amyloids. Removal of SAP through a specific aggregation mechanism mediated by multivalent ligands appears to provide therapeutic benefit in the progression of this disease. Crystallographic studies reveal that in our novel series of ligands only the methyl and carboxylate moieties of the pyruvate ketal directly interact with the protein, but the geometric constraints imposed by the tether dictate which of two chair conformations are adopted by the pyruvate dioxane ring. Solution studies, as interpreted through a simple thermodynamic model, account for the distribution of pentameric and decameric bound states at different ligand concentrations and indicate that differences in the flexibility of the tether determine the geometry and stability of the specific aggregates formed between SAP and two different bivalent ligands.
Literature
PMID:
16036920
Author(s):
Ho, J.G., Kitov, P.I., Paszkiewicz, E., Sadowska, J., Bundle, D.R., Ng, K.K.
Reference:
J Biol Chem. 2005 Sep 9;280(36):31999-2008. Epub 2005 Jul 20
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Entry:
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Structure:
PDB
CIF
FASTA
Contact Network:
CSV
JSON
Protein Information
Protein Name:
Serum amyloid P-component
Alternative Name:
9.5S alpha-1-glycoprotein
Gene Name:
APCS, PTX2
Sequence Length:
204
Species:
Homo sapiens
Mutation(s):
No
E.C. Number:
UniProt ID:
P02743
Keyword(s):
Serum amyloid P-component
Structure Information
PDB ID:
2A3X
Amyloid Category:
Non-amyloid
Type:
Aggregating complex
Global Stoichiometry:
Homo 10-mer - A10
PDB Classification:
METAL BINDING PROTEIN
Method:
X-RAY DIFFRACTION
Resolution (
Å
):
3.0
R free:
0.282
Ligand Information
Ligand ID
Chain ID
Ligand Formula
Ligand MW
Ligand Name
Ligand SMILES
InChI Key
CA
A
Ca 2
40.08
CALCIUM ION
[Ca+2]
BHPQYMZQTOCNFJ-UHFFFAOYSA-N
CA
B
Ca 2
40.08
CALCIUM ION
[Ca+2]
BHPQYMZQTOCNFJ-UHFFFAOYSA-N
CA
C
Ca 2
40.08
CALCIUM ION
[Ca+2]
BHPQYMZQTOCNFJ-UHFFFAOYSA-N
CPK
C
C18 H26 N2 O12
462.4
BIS-1,2-{[(Z)-2CARBOXY-2-METHYL-1,3-DIOXANE]-5-YLOXYCARBONYL}-PIPERAZINE
CC1(OCC(CO1)OC(=O)N2CCN(CC2)C(=O)OC3COC(OC3)(C)C(=O)O)C(=O)O
GNQQJZKGGHOMBD-RDAHUFKRSA-N
CA
D
Ca 2
40.08
CALCIUM ION
[Ca+2]
BHPQYMZQTOCNFJ-UHFFFAOYSA-N
CA
E
Ca 2
40.08
CALCIUM ION
[Ca+2]
BHPQYMZQTOCNFJ-UHFFFAOYSA-N
CA
F
Ca 2
40.08
CALCIUM ION
[Ca+2]
BHPQYMZQTOCNFJ-UHFFFAOYSA-N
CA
G
Ca 2
40.08
CALCIUM ION
[Ca+2]
BHPQYMZQTOCNFJ-UHFFFAOYSA-N
CA
H
Ca 2
40.08
CALCIUM ION
[Ca+2]
BHPQYMZQTOCNFJ-UHFFFAOYSA-N
CPK
H
C18 H26 N2 O12
462.4
BIS-1,2-{[(Z)-2CARBOXY-2-METHYL-1,3-DIOXANE]-5-YLOXYCARBONYL}-PIPERAZINE
CC1(OCC(CO1)OC(=O)N2CCN(CC2)C(=O)OC3COC(OC3)(C)C(=O)O)C(=O)O
GNQQJZKGGHOMBD-RDAHUFKRSA-N
CA
I
Ca 2
40.08
CALCIUM ION
[Ca+2]
BHPQYMZQTOCNFJ-UHFFFAOYSA-N
CPK
I
C18 H26 N2 O12
462.4
BIS-1,2-{[(Z)-2CARBOXY-2-METHYL-1,3-DIOXANE]-5-YLOXYCARBONYL}-PIPERAZINE
CC1(OCC(CO1)OC(=O)N2CCN(CC2)C(=O)OC3COC(OC3)(C)C(=O)O)C(=O)O
GNQQJZKGGHOMBD-RDAHUFKRSA-N
CA
J
Ca 2
40.08
CALCIUM ION
[Ca+2]
BHPQYMZQTOCNFJ-UHFFFAOYSA-N
Entry:S-0082
PDB ID: 2A3Y
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JSON
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Protein Contacts Atlas
Sequence & Sec. Str.
Chain 1
1
H
T
D
L
S
G
K
V
F
V
F
P
R
E
S
V
T
D
H
V
N
L
I
T
P
25
26
L
E
K
P
L
Q
N
F
T
L
C
F
R
A
Y
S
D
L
S
R
A
Y
S
L
F
50
51
S
Y
N
T
Q
G
R
D
N
E
L
L
V
Y
K
E
R
V
G
E
Y
S
L
Y
I
75
76
G
R
H
K
V
T
S
K
V
I
E
K
F
P
A
P
V
H
I
C
V
S
W
E
S
100
101
S
S
G
I
A
E
F
W
I
N
G
T
P
L
V
K
K
G
L
R
Q
G
Y
F
V
125
126
E
A
Q
P
K
I
V
L
G
Q
E
Q
D
S
Y
G
G
K
F
D
R
S
Q
S
F
150
151
V
G
E
I
G
D
L
Y
M
W
D
S
V
L
P
P
E
N
I
L
S
A
Y
Q
G
175
176
T
P
L
P
A
N
I
L
D
W
Q
A
L
N
Y
E
I
R
G
Y
V
I
I
K
P
200
201
L
V
W
V
204
Chain 2
1
H
T
D
L
S
G
K
V
F
V
F
P
R
E
S
V
T
D
H
V
N
L
I
T
P
25
26
L
E
K
P
L
Q
N
F
T
L
C
F
R
A
Y
S
D
L
S
R
A
Y
S
L
F
50
51
S
Y
N
T
Q
G
R
D
N
E
L
L
V
Y
K
E
R
V
G
E
Y
S
L
Y
I
75
76
G
R
H
K
V
T
S
K
V
I
E
K
F
P
A
P
V
H
I
C
V
S
W
E
S
100
101
S
S
G
I
A
E
F
W
I
N
G
T
P
L
V
K
K
G
L
R
Q
G
Y
F
V
125
126
E
A
Q
P
K
I
V
L
G
Q
E
Q
D
S
Y
G
G
K
F
D
R
S
Q
S
F
150
151
V
G
E
I
G
D
L
Y
M
W
D
S
V
L
P
P
E
N
I
L
S
A
Y
Q
G
175
176
T
P
L
P
A
N
I
L
D
W
Q
A
L
N
Y
E
I
R
G
Y
V
I
I
K
P
200
201
L
V
W
V
204
Chain 3
1
H
T
D
L
S
G
K
V
F
V
F
P
R
E
S
V
T
D
H
V
N
L
I
T
P
25
26
L
E
K
P
L
Q
N
F
T
L
C
F
R
A
Y
S
D
L
S
R
A
Y
S
L
F
50
51
S
Y
N
T
Q
G
R
D
N
E
L
L
V
Y
K
E
R
V
G
E
Y
S
L
Y
I
75
76
G
R
H
K
V
T
S
K
V
I
E
K
F
P
A
P
V
H
I
C
V
S
W
E
S
100
101
S
S
G
I
A
E
F
W
I
N
G
T
P
L
V
K
K
G
L
R
Q
G
Y
F
V
125
126
E
A
Q
P
K
I
V
L
G
Q
E
Q
D
S
Y
G
G
K
F
D
R
S
Q
S
F
150
151
V
G
E
I
G
D
L
Y
M
W
D
S
V
L
P
P
E
N
I
L
S
A
Y
Q
G
175
176
T
P
L
P
A
N
I
L
D
W
Q
A
L
N
Y
E
I
R
G
Y
V
I
I
K
P
200
201
L
V
W
V
204
Chain 4
1
H
T
D
L
S
G
K
V
F
V
F
P
R
E
S
V
T
D
H
V
N
L
I
T
P
25
26
L
E
K
P
L
Q
N
F
T
L
C
F
R
A
Y
S
D
L
S
R
A
Y
S
L
F
50
51
S
Y
N
T
Q
G
R
D
N
E
L
L
V
Y
K
E
R
V
G
E
Y
S
L
Y
I
75
76
G
R
H
K
V
T
S
K
V
I
E
K
F
P
A
P
V
H
I
C
V
S
W
E
S
100
101
S
S
G
I
A
E
F
W
I
N
G
T
P
L
V
K
K
G
L
R
Q
G
Y
F
V
125
126
E
A
Q
P
K
I
V
L
G
Q
E
Q
D
S
Y
G
G
K
F
D
R
S
Q
S
F
150
151
V
G
E
I
G
D
L
Y
M
W
D
S
V
L
P
P
E
N
I
L
S
A
Y
Q
G
175
176
T
P
L
P
A
N
I
L
D
W
Q
A
L
N
Y
E
I
R
G
Y
V
I
I
K
P
200
201
L
V
W
V
204
Chain 5
1
H
T
D
L
S
G
K
V
F
V
F
P
R
E
S
V
T
D
H
V
N
L
I
T
P
25
26
L
E
K
P
L
Q
N
F
T
L
C
F
R
A
Y
S
D
L
S
R
A
Y
S
L
F
50
51
S
Y
N
T
Q
G
R
D
N
E
L
L
V
Y
K
E
R
V
G
E
Y
S
L
Y
I
75
76
G
R
H
K
V
T
S
K
V
I
E
K
F
P
A
P
V
H
I
C
V
S
W
E
S
100
101
S
S
G
I
A
E
F
W
I
N
G
T
P
L
V
K
K
G
L
R
Q
G
Y
F
V
125
126
E
A
Q
P
K
I
V
L
G
Q
E
Q
D
S
Y
G
G
K
F
D
R
S
Q
S
F
150
151
V
G
E
I
G
D
L
Y
M
W
D
S
V
L
P
P
E
N
I
L
S
A
Y
Q
G
175
176
T
P
L
P
A
N
I
L
D
W
Q
A
L
N
Y
E
I
R
G
Y
V
I
I
K
P
200
201
L
V
W
V
204
Helix: Magenta; Strand: Yellow; Coil & Turn: White.
Charged residues and Proline are highlighed in blue.
Description
Pentameric crystal structure of human serum amyloid P-component bound to Bis-1,2-{[(Z)-2carboxy-2-methyl-1,3-dioxane]-5-yloxycarbamoyl}-ethane
SAP, a protein of the human innate immune system, is universally present in amyloids. Removal of SAP through a specific aggregation mechanism mediated by multivalent ligands appears to provide therapeutic benefit in the progression of this disease. Crystallographic studies reveal that in our novel series of ligands only the methyl and carboxylate moieties of the pyruvate ketal directly interact with the protein, but the geometric constraints imposed by the tether dictate which of two chair conformations are adopted by the pyruvate dioxane ring. Solution studies, as interpreted through a simple thermodynamic model, account for the distribution of pentameric and decameric bound states at different ligand concentrations and indicate that differences in the flexibility of the tether determine the geometry and stability of the specific aggregates formed between SAP and two different bivalent ligands.
Literature
PMID:
16036920
Author(s):
Ho, J.G., Kitov, P.I., Paszkiewicz, E., Sadowska, J., Bundle, D.R., Ng, K.K.
Reference:
J Biol Chem. 2005 Sep 9;280(36):31999-2008. Epub 2005 Jul 20
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Structure:
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FASTA
Contact Network:
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JSON
Protein Information
Protein Name:
Serum amyloid P-component
Alternative Name:
9.5S alpha-1-glycoprotein
Gene Name:
APCS, PTX2
Sequence Length:
204
Species:
Homo sapiens
Mutation(s):
No
E.C. Number:
UniProt ID:
P02743
Keyword(s):
Serum amyloid P-component
Structure Information
PDB ID:
2A3Y
Amyloid Category:
Non-amyloid
Type:
Aggregating complex
Global Stoichiometry:
Homo 5-mer - A5
PDB Classification:
METAL BINDING PROTEIN
Method:
X-RAY DIFFRACTION
Resolution (
Å
):
2.0
R free:
0.25
Ligand Information
Ligand ID
Chain ID
Ligand Formula
Ligand MW
Ligand Name
Ligand SMILES
InChI Key
CA
A
Ca 2
40.08
CALCIUM ION
[Ca+2]
BHPQYMZQTOCNFJ-UHFFFAOYSA-N
CPJ
A
C16 H24 N2 O12
436.37
BIS-1,2-{[(Z)-2-CARBOXY-2-METHYL-1,3-DIOXANE]-5-YLOXYCARBAMOYL}-ETHANE
CC1(OCC(CO1)OC(=O)NCCNC(=O)OC2COC(OC2)(C)C(=O)O)C(=O)O
HAVIIPIIAVTNFO-GXZHHNFCSA-N
CA
B
Ca 2
40.08
CALCIUM ION
[Ca+2]
BHPQYMZQTOCNFJ-UHFFFAOYSA-N
CPJ
B
C16 H24 N2 O12
436.37
BIS-1,2-{[(Z)-2-CARBOXY-2-METHYL-1,3-DIOXANE]-5-YLOXYCARBAMOYL}-ETHANE
CC1(OCC(CO1)OC(=O)NCCNC(=O)OC2COC(OC2)(C)C(=O)O)C(=O)O
HAVIIPIIAVTNFO-GXZHHNFCSA-N
CA
C
Ca 2
40.08
CALCIUM ION
[Ca+2]
BHPQYMZQTOCNFJ-UHFFFAOYSA-N
CPJ
C
C16 H24 N2 O12
436.37
BIS-1,2-{[(Z)-2-CARBOXY-2-METHYL-1,3-DIOXANE]-5-YLOXYCARBAMOYL}-ETHANE
CC1(OCC(CO1)OC(=O)NCCNC(=O)OC2COC(OC2)(C)C(=O)O)C(=O)O
HAVIIPIIAVTNFO-GXZHHNFCSA-N
CA
D
Ca 2
40.08
CALCIUM ION
[Ca+2]
BHPQYMZQTOCNFJ-UHFFFAOYSA-N
CPJ
D
C16 H24 N2 O12
436.37
BIS-1,2-{[(Z)-2-CARBOXY-2-METHYL-1,3-DIOXANE]-5-YLOXYCARBAMOYL}-ETHANE
CC1(OCC(CO1)OC(=O)NCCNC(=O)OC2COC(OC2)(C)C(=O)O)C(=O)O
HAVIIPIIAVTNFO-GXZHHNFCSA-N
CA
E
Ca 2
40.08
CALCIUM ION
[Ca+2]
BHPQYMZQTOCNFJ-UHFFFAOYSA-N
CPJ
E
C16 H24 N2 O12
436.37
BIS-1,2-{[(Z)-2-CARBOXY-2-METHYL-1,3-DIOXANE]-5-YLOXYCARBAMOYL}-ETHANE
CC1(OCC(CO1)OC(=O)NCCNC(=O)OC2COC(OC2)(C)C(=O)O)C(=O)O
HAVIIPIIAVTNFO-GXZHHNFCSA-N
Entry:S-0083
PDB ID: 2APQ
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Structure
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Protein Contacts Atlas
Sequence & Sec. Str.
Chain 1
1
A
M
A
K
E
T
A
A
A
K
F
E
R
Q
H
M
D
S
S
T
S
A
A
S
S
25
26
S
N
Y
C
N
Q
M
M
K
S
R
N
L
T
K
D
R
C
K
P
V
N
T
F
V
50
51
H
E
S
L
A
D
V
Q
A
V
C
S
Q
K
N
V
A
C
K
N
G
Q
T
N
C
75
76
Y
Q
S
Y
S
T
M
S
I
T
D
C
R
E
T
G
S
S
K
Y
P
N
C
A
Y
100
101
K
T
T
Q
A
N
K
H
I
I
V
A
C
E
G
G
Q
Q
Q
Q
Q
Q
Q
Q
Q
125
126
Q
G
N
P
Y
V
P
V
A
F
D
A
S
V
139
Helix: Magenta; Strand: Yellow; Coil & Turn: White.
Charged residues and Proline are highlighed in blue.
Description
Crystal Structure of an Active Site Mutant of Bovine Pancreatic Ribonuclease A (H119A-RNase A) with a 10-Glutamine expansion in the C-terminal hinge-loop
A designed amyloid-like fibril of the well-characterized enzyme RNase A contains native-like molecules capable of enzymatic activity. In addition, these functional molecular units are formed from a core RNase A domain and a swapped complementary domain. These findings are consistent with the zipper-spine model in which a cross-Beta spine is decorated with three-dimensional domain-swapped functional units, retaining native-like structure.
Literature
PMID:
16148936
Author(s):
Sambashivan, S., Liu, Y., Sawaya, M.R., Gingery, M., Eisenberg, D.
Reference:
Nature. 2005 Sep 8;437(7056):266-9
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Entry:
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Structure:
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Contact Network:
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Protein Information
Protein Name:
Ribonuclease pancreatic
Alternative Name:
RNase 1, RNase A
Gene Name:
RNASE1, RNS1
Sequence Length:
139
Species:
Bos taurus
Mutation(s):
H119A
E.C. Number:
4.6.1.18
UniProt ID:
P61823
Keyword(s):
Ribonuclease
Structure Information
PDB ID:
2APQ
Amyloid Category:
Amyloid
Type:
Protein
Global Stoichiometry:
Monomer - A
PDB Classification:
HYDROLASE
Method:
X-RAY DIFFRACTION
Resolution (
Å
):
1.8
R free:
0.215
Ligand Information
Ligand ID
Chain ID
Ligand Formula
Ligand MW
Ligand Name
Ligand SMILES
InChI Key
PO4
A
O4 P -3
94.97
PHOSPHATE ION
[O-]P(=O)([O-])[O-]
NBIIXXVUZAFLBC-UHFFFAOYSA-K
Entry:S-0084
PDB ID: 2B14
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Protein Contacts Atlas
Sequence & Sec. Str.
Chain 1
1
G
P
T
G
T
G
E
S
K
C
P
L
M
V
K
V
L
D
A
V
R
G
S
P
A
25
26
I
N
V
A
V
H
V
F
R
K
A
A
D
D
T
W
E
P
F
A
S
G
K
T
S
50
51
E
S
G
E
P
H
G
L
T
T
E
E
E
F
V
E
G
I
Y
K
V
E
I
D
T
75
76
K
S
Y
W
K
A
L
G
I
S
P
F
H
E
H
A
E
V
V
F
T
A
N
D
S
100
101
G
P
R
R
Y
T
I
A
A
L
L
S
P
Y
S
Y
S
T
T
A
V
V
T
N
P
125
126
K
E
127
Chain 2
1
G
P
T
G
T
G
E
S
K
C
P
L
M
V
K
V
L
D
A
V
R
G
S
P
A
25
26
I
N
V
A
V
H
V
F
R
K
A
A
D
D
T
W
E
P
F
A
S
G
K
T
S
50
51
E
S
G
E
P
H
G
L
T
T
E
E
E
F
V
E
G
I
Y
K
V
E
I
D
T
75
76
K
S
Y
W
K
A
L
G
I
S
P
F
H
E
H
A
E
V
V
F
T
A
N
D
S
100
101
G
P
R
R
Y
T
I
A
A
L
L
S
P
Y
S
Y
S
T
T
A
V
V
T
N
P
125
126
K
E
127
Helix: Magenta; Strand: Yellow; Coil & Turn: White.
Charged residues and Proline are highlighed in blue.
Description
The crystal structure of 2,4-dinitrophenol in complex with the amyloidogenic variant Transthyretin Leu 55 Pro
This work provides insight into the structural determinants of the highly stabilizing effects of 2,4-dinitrophenol on wild-type TTR. It is also shown that similar interactions are established between this molecule and two highly amyloidogenic TTR variants: TTR L55P and TTR Y78F. In the three crystal complexes, 2,4-dinitrophenol occupies the two hormone-binding sites of the TTR tetramer. As a result of 2,4-dinitrophenol binding, the two dimers in the TTR tetramer become closer, increasing the stability of the protein. The three-dimensional structures allowed a comprehensive description of key interactions between transthyretin and 2,4-dinitrophenol, a small compound that holds promise as a template for the design of a therapeutical drug for amyloid diseases.
Literature
PMID:
16627944
Author(s):
Morais-de-Sa, E., Neto-Silva, R.M., Pereira, P.J., Saraiva, M.J., Damas, A.M.
Reference:
Acta Crystallogr D Biol Crystallogr. 2006 May;62(Pt 5):512-9. Epub 2006 Apr 19
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Structure:
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Contact Network:
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Protein Information
Protein Name:
Transthyretin
Alternative Name:
ATTR, Prealbumin, TBPA
Gene Name:
TTR, PALB
Sequence Length:
127
Species:
Homo sapiens
Mutation(s):
L55P
E.C. Number:
UniProt ID:
P02766
Keyword(s):
Transthyretin
Structure Information
PDB ID:
2B14
Amyloid Category:
Non-amyloid
Type:
Inhibitor complex
Global Stoichiometry:
Homo 4-mer - A4
PDB Classification:
TRANSPORT PROTEIN
Method:
X-RAY DIFFRACTION
Resolution (
Å
):
2.0
R free:
0.239
Ligand Information
Ligand ID
Chain ID
Ligand Formula
Ligand MW
Ligand Name
Ligand SMILES
InChI Key
DNF
A
C6 H4 N2 O5
184.11
2,4-DINITROPHENOL
c1cc(c(cc1[N+](=O)[O-])[N+](=O)[O-])O
UFBJCMHMOXMLKC-UHFFFAOYSA-N
DNF
B
C6 H4 N2 O5
184.11
2,4-DINITROPHENOL
c1cc(c(cc1[N+](=O)[O-])[N+](=O)[O-])O
UFBJCMHMOXMLKC-UHFFFAOYSA-N
Entry:S-0085
PDB ID: 2B15
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Protein Contacts Atlas
Sequence & Sec. Str.
Chain 1
1
G
P
T
G
T
G
E
S
K
C
P
L
M
V
K
V
L
D
A
V
R
G
S
P
A
25
26
I
N
V
A
V
H
V
F
R
K
A
A
D
D
T
W
E
P
F
A
S
G
K
T
S
50
51
E
S
G
E
L
H
G
L
T
T
E
E
E
F
V
E
G
I
Y
K
V
E
I
D
T
75
76
K
S
Y
W
K
A
L
G
I
S
P
F
H
E
H
A
E
V
V
F
T
A
N
D
S
100
101
G
P
R
R
Y
T
I
A
A
L
L
S
P
Y
S
Y
S
T
T
A
V
V
T
N
P
125
126
K
E
127
Chain 2
1
G
P
T
G
T
G
E
S
K
C
P
L
M
V
K
V
L
D
A
V
R
G
S
P
A
25
26
I
N
V
A
V
H
V
F
R
K
A
A
D
D
T
W
E
P
F
A
S
G
K
T
S
50
51
E
S
G
E
L
H
G
L
T
T
E
E
E
F
V
E
G
I
Y
K
V
E
I
D
T
75
76
K
S
Y
W
K
A
L
G
I
S
P
F
H
E
H
A
E
V
V
F
T
A
N
D
S
100
101
G
P
R
R
Y
T
I
A
A
L
L
S
P
Y
S
Y
S
T
T
A
V
V
T
N
P
125
126
K
E
127
Helix: Magenta; Strand: Yellow; Coil & Turn: White.
Charged residues and Proline are highlighed in blue.
Description
The crystal structure of 2,4-dinitrophenol in complex with human transthyretin
This work provides insight into the structural determinants of the highly stabilizing effects of 2,4-dinitrophenol on wild-type TTR. It is also shown that similar interactions are established between this molecule and two highly amyloidogenic TTR variants: TTR L55P and TTR Y78F. In the three crystal complexes, 2,4-dinitrophenol occupies the two hormone-binding sites of the TTR tetramer. As a result of 2,4-dinitrophenol binding, the two dimers in the TTR tetramer become closer, increasing the stability of the protein. The three-dimensional structures allowed a comprehensive description of key interactions between transthyretin and 2,4-dinitrophenol, a small compound that holds promise as a template for the design of a therapeutical drug for amyloid diseases.
Literature
PMID:
16627944
Author(s):
Morais-de-Sa, E., Neto-Silva, R.M., Pereira, P.J., Saraiva, M.J., Damas, A.M.
Reference:
Acta Crystallogr D Biol Crystallogr. 2006 May;62(Pt 5):512-9. Epub 2006 Apr 19
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Entry:
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Structure:
PDB
CIF
FASTA
Contact Network:
CSV
JSON
Protein Information
Protein Name:
Transthyretin
Alternative Name:
ATTR, Prealbumin, TBPA
Gene Name:
TTR, PALB
Sequence Length:
127
Species:
Homo sapiens
Mutation(s):
No
E.C. Number:
UniProt ID:
P02766
Keyword(s):
Transthyretin
Structure Information
PDB ID:
2B15
Amyloid Category:
Non-amyloid
Type:
Inhibitor complex
Global Stoichiometry:
Homo 4-mer - A4
PDB Classification:
TRANSPORT PROTEIN
Method:
X-RAY DIFFRACTION
Resolution (
Å
):
1.7
R free:
0.218
Ligand Information
Ligand ID
Chain ID
Ligand Formula
Ligand MW
Ligand Name
Ligand SMILES
InChI Key
DNF
A
C6 H4 N2 O5
184.11
2,4-DINITROPHENOL
c1cc(c(cc1[N+](=O)[O-])[N+](=O)[O-])O
UFBJCMHMOXMLKC-UHFFFAOYSA-N
SO4
A
O4 S -2
96.06
SULFATE ION
[O-]S(=O)(=O)[O-]
QAOWNCQODCNURD-UHFFFAOYSA-L
DNF
B
C6 H4 N2 O5
184.11
2,4-DINITROPHENOL
c1cc(c(cc1[N+](=O)[O-])[N+](=O)[O-])O
UFBJCMHMOXMLKC-UHFFFAOYSA-N
Entry:S-0086
PDB ID: 2B16
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Structure
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Protein Contacts Atlas
Sequence & Sec. Str.
Chain 1
1
G
P
T
G
T
G
E
S
K
C
P
L
M
V
K
V
L
D
A
V
R
G
S
P
A
25
26
I
N
V
A
V
H
V
F
R
K
A
A
D
D
T
W
E
P
F
A
S
G
K
T
S
50
51
E
S
G
E
L
H
G
L
T
T
E
E
E
F
V
E
G
I
Y
K
V
E
I
D
T
75
76
K
S
F
W
K
A
L
G
I
S
P
F
H
E
H
A
E
V
V
F
T
A
N
D
S
100
101
G
P
R
R
Y
T
I
A
A
L
L
S
P
Y
S
Y
S
T
T
A
V
V
T
N
P
125
126
K
E
127
Chain 2
1
G
P
T
G
T
G
E
S
K
C
P
L
M
V
K
V
L
D
A
V
R
G
S
P
A
25
26
I
N
V
A
V
H
V
F
R
K
A
A
D
D
T
W
E
P
F
A
S
G
K
T
S
50
51
E
S
G
E
L
H
G
L
T
T
E
E
E
F
V
E
G
I
Y
K
V
E
I
D
T
75
76
K
S
F
W
K
A
L
G
I
S
P
F
H
E
H
A
E
V
V
F
T
A
N
D
S
100
101
G
P
R
R
Y
T
I
A
A
L
L
S
P
Y
S
Y
S
T
T
A
V
V
T
N
P
125
126
K
E
127
Helix: Magenta; Strand: Yellow; Coil & Turn: White.
Charged residues and Proline are highlighed in blue.
Description
The crystal structure of 2,4-dinitrophenol in complex with the amyloidogenic variant Transthyretin Tyr78Phe
This work provides insight into the structural determinants of the highly stabilizing effects of 2,4-dinitrophenol on wild-type TTR. It is also shown that similar interactions are established between this molecule and two highly amyloidogenic TTR variants: TTR L55P and TTR Y78F. In the three crystal complexes, 2,4-dinitrophenol occupies the two hormone-binding sites of the TTR tetramer. As a result of 2,4-dinitrophenol binding, the two dimers in the TTR tetramer become closer, increasing the stability of the protein. The three-dimensional structures allowed a comprehensive description of key interactions between transthyretin and 2,4-dinitrophenol, a small compound that holds promise as a template for the design of a therapeutical drug for amyloid diseases.
Literature
PMID:
16627944
Author(s):
Morais-de-Sa, E., Neto-Silva, R.M., Pereira, P.J., Saraiva, M.J., Damas, A.M.
Reference:
Acta Crystallogr D Biol Crystallogr. 2006 May;62(Pt 5):512-9. Epub 2006 Apr 19
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Entry:
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Structure:
PDB
CIF
FASTA
Contact Network:
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Protein Information
Protein Name:
Transthyretin
Alternative Name:
ATTR, Prealbumin, TBPA
Gene Name:
TTR, PALB
Sequence Length:
127
Species:
Homo sapiens
Mutation(s):
Y78F
E.C. Number:
UniProt ID:
P02766
Keyword(s):
Transthyretin
Structure Information
PDB ID:
2B16
Amyloid Category:
Non-amyloid
Type:
Inhibitor complex
Global Stoichiometry:
Homo 4-mer - A4
PDB Classification:
TRANSPORT PROTEIN
Method:
X-RAY DIFFRACTION
Resolution (
Å
):
1.75
R free:
0.23600000
Ligand Information
Ligand ID
Chain ID
Ligand Formula
Ligand MW
Ligand Name
Ligand SMILES
InChI Key
DNF
A
C6 H4 N2 O5
184.11
2,4-DINITROPHENOL
c1cc(c(cc1[N+](=O)[O-])[N+](=O)[O-])O
UFBJCMHMOXMLKC-UHFFFAOYSA-N
DNF
B
C6 H4 N2 O5
184.11
2,4-DINITROPHENOL
c1cc(c(cc1[N+](=O)[O-])[N+](=O)[O-])O
UFBJCMHMOXMLKC-UHFFFAOYSA-N
Entry:S-0087
PDB ID: 2B77
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Structure
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Protein Contacts Atlas
Sequence & Sec. Str.
Chain 1
1
G
P
T
G
T
G
E
S
K
C
P
L
M
V
K
V
L
D
A
V
R
G
S
P
A
25
26
I
N
V
A
V
H
V
F
R
K
A
A
D
D
T
W
E
P
F
A
S
G
K
T
S
50
51
E
S
G
E
L
H
G
L
T
T
E
E
E
F
V
E
G
I
Y
K
V
E
I
D
T
75
76
K
S
Y
W
K
A
L
G
I
S
P
F
H
E
H
A
E
V
V
F
T
A
N
D
S
100
101
G
P
R
R
Y
T
I
A
A
L
L
S
P
Y
S
Y
S
T
T
A
V
V
T
N
P
125
126
K
E
127
Chain 2
1
G
P
T
G
T
G
E
S
K
C
P
L
M
V
K
V
L
D
A
V
R
G
S
P
A
25
26
I
N
V
A
V
H
V
F
R
K
A
A
D
D
T
W
E
P
F
A
S
G
K
T
S
50
51
E
S
G
E
L
H
G
L
T
T
E
E
E
F
V
E
G
I
Y
K
V
E
I
D
T
75
76
K
S
Y
W
K
A
L
G
I
S
P
F
H
E
H
A
E
V
V
F
T
A
N
D
S
100
101
G
P
R
R
Y
T
I
A
A
L
L
S
P
Y
S
Y
S
T
T
A
V
V
T
N
P
125
126
K
E
127
Helix: Magenta; Strand: Yellow; Coil & Turn: White.
Charged residues and Proline are highlighed in blue.
Description
Human transthyretin (TTR) complexed with Diflunisal analogues- TTR.2',4'-DICHLORO-4-HYDROXY-1,1'-BIPHENYL-3-CARBOXYLIC ACID
Analogues of diflunisal, an FDA-approved nonsteroidal antiinflammatory drug (NSAID), were synthesized and evaluated as inhibitors of transthyretin (TTR) aggregation, including amyloid fibril formation. Biophysical studies reveal that inhibitors dramatically slow tetramer dissociation (the rate-determining step of amyloidogenesis) over a duration of 168 h. This appears to be achieved through ground-state stabilization, which raises the kinetic barrier for tetramer dissociation.
Literature
PMID:
14711308
Author(s):
Adamski-Werner, S.L., Palaninathan, S.K., Sacchettini, J.C., Kelly, J.W.
Reference:
J Med Chem. 2004 Jan 15;47(2):355-74
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Entry:
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Structure:
PDB
CIF
FASTA
Contact Network:
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Protein Information
Protein Name:
Transthyretin
Alternative Name:
ATTR, Prealbumin, TBPA
Gene Name:
TTR, PALB
Sequence Length:
127
Species:
Homo sapiens
Mutation(s):
No
E.C. Number:
UniProt ID:
P02766
Keyword(s):
Transthyretin
Structure Information
PDB ID:
2B77
Amyloid Category:
Non-amyloid
Type:
Inhibitor complex
Global Stoichiometry:
Homo 4-mer - A4
PDB Classification:
HORMONE/GROWTH FACTOR
Method:
X-RAY DIFFRACTION
Resolution (
Å
):
1.7
R free:
0.23800000
Ligand Information
Ligand ID
Chain ID
Ligand Formula
Ligand MW
Ligand Name
Ligand SMILES
InChI Key
3CA
A
C13 H8 Cl2 O3
283.11
2',4'-DICHLORO-4-HYDROXY-1,1'-BIPHENYL-3-CARBOXYLIC ACID
c1cc(c(cc1c2ccc(cc2Cl)Cl)C(=O)O)O
SKAFZYDMDHPPJM-UHFFFAOYSA-N
3CA
B
C13 H8 Cl2 O3
283.11
2',4'-DICHLORO-4-HYDROXY-1,1'-BIPHENYL-3-CARBOXYLIC ACID
c1cc(c(cc1c2ccc(cc2Cl)Cl)C(=O)O)O
SKAFZYDMDHPPJM-UHFFFAOYSA-N
Entry:S-0088
PDB ID: 2B9A
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Structure
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Protein Contacts Atlas
Sequence & Sec. Str.
Chain 1
1
G
P
T
G
T
G
E
S
K
C
P
L
M
V
K
V
L
D
A
V
R
G
S
P
A
25
26
I
N
V
A
V
H
V
F
R
K
A
A
D
D
T
W
E
P
F
A
S
G
K
T
S
50
51
E
S
G
E
L
H
G
L
T
T
E
E
E
F
V
E
G
I
Y
K
V
E
I
D
T
75
76
K
S
Y
W
K
A
L
G
I
S
P
F
H
E
H
A
E
V
V
F
T
A
N
D
S
100
101
G
P
R
R
Y
T
I
A
A
L
L
S
P
Y
S
Y
S
T
T
A
V
V
T
N
P
125
126
K
E
127
Chain 2
1
G
P
T
G
T
G
E
S
K
C
P
L
M
V
K
V
L
D
A
V
R
G
S
P
A
25
26
I
N
V
A
V
H
V
F
R
K
A
A
D
D
T
W
E
P
F
A
S
G
K
T
S
50
51
E
S
G
E
L
H
G
L
T
T
E
E
E
F
V
E
G
I
Y
K
V
E
I
D
T
75
76
K
S
Y
W
K
A
L
G
I
S
P
F
H
E
H
A
E
V
V
F
T
A
N
D
S
100
101
G
P
R
R
Y
T
I
A
A
L
L
S
P
Y
S
Y
S
T
T
A
V
V
T
N
P
125
126
K
E
127
Helix: Magenta; Strand: Yellow; Coil & Turn: White.
Charged residues and Proline are highlighed in blue.
Description
Human transthyretin (TTR) complexed with diflunisal analogues- TTR.3',5'-difluorobiphenyl-4-carboxylic acid
Analogues of diflunisal, an FDA-approved nonsteroidal antiinflammatory drug (NSAID), were synthesized and evaluated as inhibitors of transthyretin (TTR) aggregation, including amyloid fibril formation. Biophysical studies reveal that inhibitors dramatically slow tetramer dissociation (the rate-determining step of amyloidogenesis) over a duration of 168 h. This appears to be achieved through ground-state stabilization, which raises the kinetic barrier for tetramer dissociation.
Literature
PMID:
14711308
Author(s):
Adamski-Werner, S.L., Palaninathan, S.K., Sacchettini, J.C., Kelly, J.W.
Reference:
J Med Chem. 2004 Jan 15;47(2):355-74
Download
Entry:
CSV
JSON
Structure:
PDB
CIF
FASTA
Contact Network:
CSV
JSON
Protein Information
Protein Name:
Transthyretin
Alternative Name:
ATTR, Prealbumin, TBPA
Gene Name:
TTR, PALB
Sequence Length:
127
Species:
Homo sapiens
Mutation(s):
No
E.C. Number:
UniProt ID:
P02766
Keyword(s):
Transthyretin
Structure Information
PDB ID:
2B9A
Amyloid Category:
Non-amyloid
Type:
Inhibitor complex
Global Stoichiometry:
Homo 4-mer - A4
PDB Classification:
HORMONE/GROWTH FACTOR
Method:
X-RAY DIFFRACTION
Resolution (
Å
):
1.54
R free:
0.24600000
Ligand Information
Ligand ID
Chain ID
Ligand Formula
Ligand MW
Ligand Name
Ligand SMILES
InChI Key
FBC
A
C13 H8 F2 O2
234.2
3',5'-DIFLUOROBIPHENYL-4-CARBOXYLIC ACID
c1cc(ccc1c2cc(cc(c2)F)F)C(=O)O
VCEFNMHMLWBFNV-UHFFFAOYSA-N
FBC
B
C13 H8 F2 O2
234.2
3',5'-DIFLUOROBIPHENYL-4-CARBOXYLIC ACID
c1cc(ccc1c2cc(cc(c2)F)F)C(=O)O
VCEFNMHMLWBFNV-UHFFFAOYSA-N
Entry:S-0089
PDB ID: 2BEG
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Structure
Press 'p' to pause
View interactive contact network
Sequence & Sec. Str.
Chain 1
1
D
A
E
F
R
H
D
S
G
Y
E
V
H
H
Q
K
L
V
F
F
A
E
D
V
G
25
26
S
N
K
G
A
I
I
G
L
M
V
G
G
V
V
I
A
42
Chain 2
1
D
A
E
F
R
H
D
S
G
Y
E
V
H
H
Q
K
L
V
F
F
A
E
D
V
G
25
26
S
N
K
G
A
I
I
G
L
M
V
G
G
V
V
I
A
42
Chain 3
1
D
A
E
F
R
H
D
S
G
Y
E
V
H
H
Q
K
L
V
F
F
A
E
D
V
G
25
26
S
N
K
G
A
I
I
G
L
M
V
G
G
V
V
I
A
42
Chain 4
1
D
A
E
F
R
H
D
S
G
Y
E
V
H
H
Q
K
L
V
F
F
A
E
D
V
G
25
26
S
N
K
G
A
I
I
G
L
M
V
G
G
V
V
I
A
42
Chain 5
1
D
A
E
F
R
H
D
S
G
Y
E
V
H
H
Q
K
L
V
F
F
A
E
D
V
G
25
26
S
N
K
G
A
I
I
G
L
M
V
G
G
V
V
I
A
42
Helix: Magenta; Strand: Yellow; Coil & Turn: White.
Charged residues and Proline are highlighed in blue.
Description
3D Structure of Alzheimer's Abeta(1-42) fibrils
The 3D structure of the fibrils comprising ABeta(1-42), which was obtained by using hydrogen-bonding constraints from quenched hydrogen/deuterium-exchange NMR, side-chain packing constraints from pairwise mutagenesis studies, and parallel, in-register Beta-sheet arrangement from previous solid-state NMR studies. Although residues 1-17 are disordered, residues 18-42 form a Beta-strand-turn-Beta-strand motif that contains two intermolecular, parallel, in-register Beta-sheets that are formed by residues 18-26 (Beta1) and 31-42 (Beta2). At least two molecules of ABeta(1-42) are required to achieve the repeating structure of a protofilament. Intermolecular side-chain contacts are formed between the odd-numbered residues of strand Beta1 of the nth molecule and the even-numbered residues of strand Beta2 of the (n - 1)th molecule. This interaction pattern leads to partially unpaired Beta-strands at the fibrillar ends, which explains the sequence selectivity, the cooperativity, and the apparent unidirectionality of ABeta fibril growth. It also provides a structural basis for fibrillization inhibitors.
Literature
PMID:
16293696
Author(s):
Luhrs, T., Ritter, C., Adrian, M., Riek-Loher, D., Bohrmann, B., Dobeli, H., Schubert, D., Riek, R.
Reference:
Proc Natl Acad Sci U S A. 2005 Nov 29;102(48):17342-7. Epub 2005 Nov 17
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Entry:
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Structure:
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FASTA
Contact Network:
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Protein Information
Protein Name:
Amyloid-beta A4 protein
Alternative Name:
ABPP, APPI, Alzheimer disease amyloid protein, Amyloid precursor protein, Amyloid-beta precursor protein, Cerebral vascular amyloid peptide, PreA4, Protease nexin-II
Gene Name:
APP, A4, AD1
Sequence Length:
42
Species:
Homo sapiens
Mutation(s):
No
E.C. Number:
UniProt ID:
P05067
Keyword(s):
Amyloid beta A4 protein
Structure Information
PDB ID:
2BEG
Amyloid Category:
Amyloid
Type:
Fibril
Global Stoichiometry:
Homo 5-mer - A5
PDB Classification:
PROTEIN FIBRIL
Method:
SOLUTION NMR
Resolution (
Å
):
R free:
Entry:S-0090
PDB ID: 2BFI
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