2qlb

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Revision as of 21:27, 12 November 2007

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spinqualitylabelsall models 2qlb, resolution 2.25Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

Crystal Structure of caspase-7 with inhibitor AC-ESMD-CHO

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.

About this Structure

2QLB is a Protein complex structure of sequences from Homo sapiens with ACE and CIT as ligands. Active as Hydrolase, with EC number 3.4.22 Full crystallographic information is available from OCA.

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:17697120

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