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J Mol Biol. 2004 Nov 5;343(5):1313-26.

Crystal structures of calpain-E64 and -leupeptin inhibitor complexes reveal mobile loops gating the active site.

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  • 1Department of Biochemistry, Queen's University, Kingston, Ont. K7L 3N6, Canada.

Abstract

The endogenous calpain inhibitor, calpastatin, modulates some patho-physiological aspects of calpain signaling. Excess calpain can escape this inhibition and as well, many calpain isoforms and autolytically generated protease core fragments are not inhibited by calpastatin. There is a need, therefore, to develop specific, cell-permeable calpain inhibitors to block uncontrolled proteolysis and prevent tissue damage during brain and heart ischemia, spinal-cord injury and Alzheimer's diseases. Here, we report the first high-resolution crystal structures of rat mu-calpain protease core complexed with two traditional, low molecular mass inhibitors, leupeptin and E64. These structures show that access to a slightly deeper, but otherwise papain-like active site is gated by two flexible loops. These loops are divergent among the calpain isoforms giving a potential structural basis for substrate/inhibitor selectivity over other papain-like cysteine proteases and between members of the calpain family.

PMID:
15491615
DOI:
10.1016/j.jmb.2004.09.016
[PubMed - indexed for MEDLINE]
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