Document Detail

In silico identification and crystal structure validation of caspase-3 inhibitors without a P1 aspartic acid moiety.
MedLine Citation:
PMID:  21821879     Owner:  NLM     Status:  MEDLINE    
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.
Rajkumar Ganesan; Stjepan Jelakovic; Peer R E Mittl; Amedeo Caflisch; Markus G Grütter
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2011-07-13
Journal Detail:
Title:  Acta crystallographica. Section F, Structural biology and crystallization communications     Volume:  67     ISSN:  1744-3091     ISO Abbreviation:  Acta Crystallogr. Sect. F Struct. Biol. Cryst. Commun.     Publication Date:  2011 Aug 
Date Detail:
Created Date:  2011-08-08     Completed Date:  2011-10-14     Revised Date:  2013-06-28    
Medline Journal Info:
Nlm Unique ID:  101226117     Medline TA:  Acta Crystallogr Sect F Struct Biol Cryst Commun     Country:  England    
Other Details:
Languages:  eng     Pagination:  842-50     Citation Subset:  IM    
Department of Biochemistry, University of Zürich, Zürich, Switzerland.
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MeSH Terms
Aspartic Acid / chemistry
Caspase 3 / chemistry*
Caspase Inhibitors
Computational Biology
Crystallography, X-Ray
Enzyme Inhibitors / chemistry*
Models, Molecular
Protein Structure, Tertiary
Reg. No./Substance:
0/Caspase Inhibitors; 0/Enzyme Inhibitors; 56-84-8/Aspartic Acid; EC 3.4.22.-/CASP3 protein, human; EC 3.4.22.-/Caspase 3

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