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- W2163887032 abstract "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." @default.
- W2163887032 created "2016-06-24" @default.
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- W2163887032 date "2008-08-15" @default.
- W2163887032 modified "2023-10-16" @default.
- W2163887032 title "Cocrystal Structures of Primed Side-Extending α-Ketoamide Inhibitors Reveal Novel Calpain-Inhibitor Aromatic Interactions" @default.
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- W2163887032 doi "https://doi.org/10.1021/jm800045t" @default.
- W2163887032 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/2631982" @default.
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