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


Ganesan, R; Jelakovic, S; Mittl, P R E; Caflisch, A; Grütter, M G (2011). In silico identification and crystal structure validation of caspase-3 inhibitors without a P1 aspartic acid moiety. Acta Crystallographica. Section F, Structural Biology and Crystallization Communications, 67(Pt 8):842-850.

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.

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.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Department of Biochemistry
07 Faculty of Science > Department of Biochemistry
Dewey Decimal Classification:570 Life sciences; biology
Scopus Subject Areas:Life Sciences > Biophysics
Life Sciences > Structural Biology
Life Sciences > Biochemistry
Life Sciences > Genetics
Physical Sciences > Condensed Matter Physics
Language:English
Date:2011
Deposited On:24 Aug 2011 15:01
Last Modified:01 Jun 2021 03:13
Publisher:International Union of Crystallography/Blackwell
ISSN:1744-3091
OA Status:Green
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1107/S1744309111018604
PubMed ID:21821879

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