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PDBsum entry 2r9c
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References listed in PDB file
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Key reference
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Title
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Cocrystal structures of primed side-Extending alpha-Ketoamide inhibitors reveal novel calpain-Inhibitor aromatic interactions.
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Authors
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J.Qian,
D.Cuerrier,
P.L.Davies,
Z.Li,
J.C.Powers,
R.L.Campbell.
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Ref.
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J Med Chem, 2008,
51,
5264-5270.
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PubMed id
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Abstract
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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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