2ql7: Difference between revisions

Revision as of 19:40, 21 February 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 with and as ligands. Active as Hydrolase, with EC number 3.4.22 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

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 ==Overview==
-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.
+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 Structure==
@@ Line 10: / Line 10: @@
 ==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 Aug 14;. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=17697120 17697120]
+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://ispc.weizmann.ac.il//pmbin/getpm?pmid=17697120 17697120]
 [[Category: Homo sapiens]]
 [[Category: Hydrolase]]
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 [[Category: zymogen]]
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jan 23 12:58:19 2008''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 18:40:16 2008''