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PLoS One. 2012;7(12):e50864. doi: 10.1371/journal.pone.0050864. Epub 2012 Dec 5.

Mechanistic and structural understanding of uncompetitive inhibitors of caspase-6.

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1
Department of Biochemical and Cellular Pharmacology, Genentech, Inc, South San Francisco, California, United States of America. heise.christopher@gene.com

Abstract

Inhibition of caspase-6 is a potential therapeutic strategy for some neurodegenerative diseases, but it has been difficult to develop selective inhibitors against caspases. We report the discovery and characterization of a potent inhibitor of caspase-6 that acts by an uncompetitive binding mode that is an unprecedented mechanism of inhibition against this target class. Biochemical assays demonstrate that, while exquisitely selective for caspase-6 over caspase-3 and -7, the compound's inhibitory activity is also dependent on the amino acid sequence and P1' character of the peptide substrate. The crystal structure of the ternary complex of caspase-6, substrate-mimetic and an 11 nM inhibitor reveals the molecular basis of inhibition. The general strategy to develop uncompetitive inhibitors together with the unique mechanism described herein provides a rationale for engineering caspase selectivity.

PMID:
23227217
PMCID:
PMC3515450
DOI:
10.1371/journal.pone.0050864
[Indexed for MEDLINE]
Free PMC Article
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