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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
17
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pubmed:dateCreated |
2008-9-8
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pubmed:abstractText |
Calpains are intracellular cysteine proteases that catalyze the cleavage of target proteins in response to Ca(2+) signaling. When Ca(2+) homeostasis is disrupted, calpain overactivation causes unregulated proteolysis, which can contribute to diseases such as postischemic injury and cataract formation. Potent calpain inhibitors exist, but of these many cross-react with other cysteine proteases and will need modification to specifically target calpain. Here, we present crystal structures of rat calpain 1 protease core (muI-II) bound to two alpha-ketoamide-based calpain inhibitors containing adenyl and piperazyl primed-side extensions. An unexpected aromatic-stacking interaction is observed between the primed-side adenine moiety and the Trp298 side chain. This interaction increased the potency of the inhibitor toward muI-II and heterodimeric m-calpain. Moreover, stacking orients the adenine such that it can be used as a scaffold for designing novel primed-side address regions, which could be incorporated into future inhibitors to enhance their calpain specificity.
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pubmed:grant |
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pubmed:commentsCorrections |
http://linkedlifedata.com/resource/pubmed/commentcorrection/18702462-10089417,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18702462-10217141,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18702462-10385126,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18702462-10476871,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18702462-10601010,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18702462-11032966,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18702462-11328585,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18702462-11342050,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18702462-11551918,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18702462-11893336,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18702462-12475205,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18702462-12843408,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18702462-14581465,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18702462-14695821,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18702462-15272157,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18702462-15299374,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18702462-15491615,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18702462-15572765,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18702462-16216885,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18702462-16369096,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18702462-16411745,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18702462-16472152,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18702462-16520377,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18702462-16768440,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18702462-17004834,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18702462-17157313,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18702462-17581577,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18702462-7984237,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18702462-8230139,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18702462-8831774,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18702462-8891101,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18702462-9245600,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18702462-9716128
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
Sep
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pubmed:issn |
1520-4804
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pubmed:author |
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pubmed:issnType |
Electronic
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pubmed:day |
11
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pubmed:volume |
51
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
5264-70
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pubmed:dateRevised |
2011-9-26
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pubmed:meshHeading |
pubmed-meshheading:18702462-Amino Acids, Aromatic,
pubmed-meshheading:18702462-Animals,
pubmed-meshheading:18702462-Calpain,
pubmed-meshheading:18702462-Carbamates,
pubmed-meshheading:18702462-Crystallography, X-Ray,
pubmed-meshheading:18702462-Dipeptides,
pubmed-meshheading:18702462-Glycoproteins,
pubmed-meshheading:18702462-Protein Conformation,
pubmed-meshheading:18702462-Rats,
pubmed-meshheading:18702462-Structure-Activity Relationship
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pubmed:year |
2008
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pubmed:articleTitle |
Cocrystal structures of primed side-extending alpha-ketoamide inhibitors reveal novel calpain-inhibitor aromatic interactions.
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pubmed:affiliation |
Department of Biochemistry, Queen's University, Kingston, Ontario, K7L 3N6, Canada.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't,
Research Support, N.I.H., Extramural
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