2ql7: Difference between revisions

Revision as of 13:31, 30 April 2008

Crystal Structure of Caspase-7 with inhibitor AC-IEPD-CHO

OverviewOverview

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.

About this StructureAbout this Structure

2QL7 is a Protein complex structure of sequences from Homo sapiens. Full crystallographic information is available from OCA.

ReferenceReference

Plasticity of S2-S4 specificity pockets of executioner caspase-7 revealed by structural and kinetic analysis., Agniswamy J, Fang B, Weber IT, FEBS J. 2007 Sep;274(18):4752-65. Epub 2007 Aug 14. PMID:17697120 Page seeded by OCA on Wed Apr 30 13:31:41 2008

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OCA

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 [[Image:2ql7.jpg|left|200px]]
- {{Structure
+<!--
-|PDB= 2ql7 |SIZE=350|CAPTION= <scene name='initialview01'>2ql7</scene>, resolution 2.4&Aring;
+The line below this paragraph, containing "STRUCTURE_2ql7", creates the "Structure Box" on the page.
-|SITE=
+You may change the PDB parameter (which sets the PDB file loaded into the applet)
-|LIGAND= <scene name='pdbligand=ACE:ACETYL+GROUP'>ACE</scene>, <scene name='pdbligand=ASA:ASPARTIC+ALDEHYDE'>ASA</scene>, <scene name='pdbligand=CIT:CITRIC+ACID'>CIT</scene>
+or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
-|ACTIVITY= <span class='plainlinks'>[http://en.wikipedia.org/wiki/Hydrolase Hydrolase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.22 3.4.22] </span>
+or leave the SCENE parameter empty for the default display.
-|GENE= CASP7, MCH3 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])
+-->
-|DOMAIN=
+{{STRUCTURE_2ql7|  PDB=2ql7  |  SCENE=  }}
-|RELATEDENTRY=[[2ql5|2QL5]], [[2ql9|2QL9]], [[2qlb|2QLB]], [[2qlf|2QLF]], [[2qlj|2QLJ]]
-|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2ql7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2ql7 OCA], [http://www.ebi.ac.uk/pdbsum/2ql7 PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2ql7 RCSB]</span>
-}}
 '''Crystal Structure of Caspase-7 with inhibitor AC-IEPD-CHO'''
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 ==Reference==
 Plasticity of S2-S4 specificity pockets of executioner caspase-7 revealed by structural and kinetic analysis., Agniswamy J, Fang B, Weber IT, FEBS J. 2007 Sep;274(18):4752-65. Epub 2007 Aug 14. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/17697120 17697120]
+[[Category: Caspase-7]]
 [[Category: Homo sapiens]]
-[[Category: Hydrolase]]
 [[Category: Protein complex]]
 [[Category: Agniswamy, J.]]
 [[Category: Fang, B.]]
 [[Category: Weber, I.]]
-[[Category: alternative splicing]]
+[[Category: Alternative splicing]]
-[[Category: apoptosis]]
+[[Category: Apoptosis]]
-[[Category: caspase-7]]
+[[Category: Caspase-7]]
-[[Category: cysteine protease]]
+[[Category: Cysteine protease]]
-[[Category: cytoplasm]]
+[[Category: Cytoplasm]]
-[[Category: hydrolase]]
+[[Category: Hydrolase]]
-[[Category: thiol protease]]
+[[Category: Thiol protease]]
-[[Category: zymogen]]
+[[Category: Zymogen]]
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Apr 30 13:31:41 2008''
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 04:50:30 2008''