In silico identification and crystal structure validation of caspase-3 inhibitors without a P1 aspartic acid moiety

TitleIn silico identification and crystal structure validation of caspase-3 inhibitors without a P1 aspartic acid moiety
Publication TypeJournal Article
Year of Publication2011
AuthorsGanesan R., Jelaković S., Mittl P.RE, Caflisch A., Grütter M.G
JournalActa Crystallographica Section F Structural Biology and Crystallization Communications
Volume67
IssuePt 8
Pagination842-850
Date Published2011 Aug 1
Type of ArticleResearch Article
ISSN1744-3091
KeywordsAspartic Acid, Caspase 3, Caspase Inhibitors, computational biology, Crystallography, X-Ray, Enzyme Inhibitors, Humans, Models, Molecular, Protein Structure, Tertiary
Abstract

Using a fragment-based docking procedure, several small-molecule inhibitors of caspase-3 were identified and tested and the crystal structures of three inhibitor complexes were determined. The crystal structures revealed that one inhibitor (NSC 18508) occupies only the S1 subsite, while two other inhibitors (NSC 89167 and NSC 251810) bind only to the prime part of the substrate-binding site. One of the major conformational changes observed in all three caspase-3-inhibitor complexes is a rotation of the Tyr204 side chain, which blocks the S2 subsite. In addition, the structural variability of the residues shaping the S1-S4 as well as the S1' subsites supports an induced-fit mechanism for the binding of the inhibitors in the active site. The high-resolution crystal structures reported here provide novel insights into the architecture of the substrate-binding site, which might be useful for the design of more potent caspase inhibitors.

DOI10.1107/S1744309111018604
pubindex

0146

Alternate JournalActa Crystallogr. Sect. F Struct. Biol. Cryst. Commun.
PubMed ID21821879
PubMed Central IDPMC3151112
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