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* Residue conservation analysis
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PDB id:
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Hydrolase/hydrolase inhibitor
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Title:
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Crystal structure of caspase-7 with inhibitor ac-dmqd-cho
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Structure:
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Caspase-7. Chain: a, c. Fragment: p20 subunit. Synonym: casp-7, ice-like apoptotic protease 3, ice-lap3, apoptotic protease mch-3, cmh-1. Engineered: yes. Caspase-7. Chain: b, d. Fragment: p10 subunit.
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: casp7, mch3. Expressed in: escherichia coli bl21. Expression_system_taxid: 511693. Synthetic: yes. Synthetic: yes
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Resolution:
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2.34Å
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R-factor:
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0.212
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R-free:
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0.233
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Authors:
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J.Agniswamy,B.Fang,I.Weber
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Key ref:
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J.Agniswamy
et al.
(2007).
Plasticity of S2-S4 specificity pockets of executioner caspase-7 revealed by structural and kinetic analysis.
Febs J,
274,
4752-4765.
PubMed id:
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Date:
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12-Jul-07
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Release date:
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28-Aug-07
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PROCHECK
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Headers
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References
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Febs J
274:4752-4765
(2007)
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PubMed id:
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Plasticity of S2-S4 specificity pockets of executioner caspase-7 revealed by structural and kinetic analysis.
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J.Agniswamy,
B.Fang,
I.T.Weber.
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ABSTRACT
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Many protein substrates of caspases are cleaved at noncanonical sites in
comparison to the recognition motifs reported for the three caspase subgroups.
To provide insight into the specificity and aid in the design of drugs to
control cell death, crystal structures of caspase-7 were determined in complexes
with six peptide analogs (Ac-DMQD-Cho, Ac-DQMD-Cho, Ac-DNLD-Cho, Ac-IEPD-Cho,
Ac-ESMD-Cho, Ac-WEHD-Cho) that span the major recognition motifs of the three
subgroups. The crystal structures show that the S2 pocket of caspase-7 can
accommodate diverse residues. Glu is not required at the P3 position because
Ac-DMQD-Cho, Ac-DQMD-Cho and Ac-DNLD-Cho with varied P3 residues are almost as
potent as the canonical Ac-DEVD-Cho. P4 Asp was present in the better inhibitors
of caspase-7. However, the S4 pocket of executioner caspase-7 has alternate
regions for binding of small branched aliphatic or polar residues similar to
those of initiator caspase-8. The observed plasticity of the caspase subsites
agrees very well with the reported cleavage of many proteins at noncanonical
sites. The results imply that factors other than the P4-P1 sequence, such as
exosites, contribute to the in vivo substrate specificity of caspases. The novel
peptide binding site identified on the molecular surface of the current
structures is suggested to be an exosite of caspase-7. These results should be
considered in the design of selective small molecule inhibitors of this
pharmacologically important protease.
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Literature references that cite this PDB file's key reference
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PubMed id
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Reference
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B.Edelmann,
U.Bertsch,
V.Tchikov,
S.Winoto-Morbach,
C.Perrotta,
M.Jakob,
S.Adam-Klages,
D.Kabelitz,
and
S.Schütze
(2011).
Caspase-8 and caspase-7 sequentially mediate proteolytic activation of acid sphingomyelinase in TNF-R1 receptosomes.
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EMBO J,
30,
379-394.
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D.Boucher,
V.Blais,
M.Drag,
and
J.B.Denault
(2011).
Molecular determinants involved in activation of caspase 7.
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Biosci Rep,
31,
283-294.
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B.Fang,
G.Fu,
J.Agniswamy,
R.W.Harrison,
and
I.T.Weber
(2009).
Caspase-3 binds diverse P4 residues in peptides as revealed by crystallography and structural modeling.
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Apoptosis,
14,
741-752.
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PDB codes:
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D.Demon,
P.Van Damme,
T.Vanden Berghe,
A.Deceuninck,
J.Van Durme,
J.Verspurten,
K.Helsens,
F.Impens,
M.Wejda,
J.Schymkowitz,
F.Rousseau,
A.Madder,
J.Vandekerckhove,
W.Declercq,
K.Gevaert,
and
P.Vandenabeele
(2009).
Proteome-wide substrate analysis indicates substrate exclusion as a mechanism to generate caspase-7 versus caspase-3 specificity.
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Mol Cell Proteomics,
8,
2700-2714.
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D.Demon,
P.Van Damme,
T.Vanden Berghe,
J.Vandekerckhove,
W.Declercq,
K.Gevaert,
and
P.Vandenabeele
(2009).
Caspase substrates: easily caught in deep waters?
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Trends Biotechnol,
27,
680-688.
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J.A.Hardy,
and
J.A.Wells
(2009).
Dissecting an allosteric switch in caspase-7 using chemical and mutational probes.
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J Biol Chem,
284,
26063-26069.
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J.Agniswamy,
B.Fang,
and
I.T.Weber
(2009).
Conformational similarity in the activation of caspase-3 and -7 revealed by the unliganded and inhibited structures of caspase-7.
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Apoptosis,
14,
1135-1144.
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PDB codes:
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L.J.Wee,
J.C.Tong,
T.W.Tan,
and
S.Ranganathan
(2009).
A multi-factor model for caspase degradome prediction.
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BMC Genomics,
10,
S6.
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W.A.Witkowski,
and
J.A.Hardy
(2009).
L2' loop is critical for caspase-7 active site formation.
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Protein Sci,
18,
1459-1468.
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PDB code:
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G.Fu,
A.A.Chumanevich,
J.Agniswamy,
B.Fang,
R.W.Harrison,
and
I.T.Weber
(2008).
Structural basis for executioner caspase recognition of P5 position in substrates.
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Apoptosis,
13,
1291-1302.
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PDB codes:
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J.Q.Du,
J.Wu,
H.J.Zhang,
Y.H.Zhang,
B.Y.Qiu,
F.Wu,
Y.H.Chen,
J.Y.Li,
F.J.Nan,
J.P.Ding,
and
J.Li
(2008).
Isoquinoline-1,3,4-trione Derivatives Inactivate Caspase-3 by Generation of Reactive Oxygen Species.
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J Biol Chem,
283,
30205-30215.
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PDB codes:
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The most recent references are shown first.
Citation data come partly from CiteXplore and partly
from an automated harvesting procedure. Note that this is likely to be
only a partial list as not all journals are covered by
either method. However, we are continually building up the citation data
so more and more references will be included with time.
Where a reference describes a PDB structure, the PDB
codes are
shown on the right.
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Links
