2R9C

Calpain 1 proteolytic core inactivated by ZLAK-3001, an alpha-ketoamide

2R9C の概要

• エントリーDOI: 10.2210/pdb2r9c/pdb
• 関連するPDBエントリー: 1kxr 1tl9 1tlo 2g8e 2g8j 2R9F
• 分子名称: Calpain-1 catalytic subunit, CALCIUM ION, CHLORIDE ION, ... (6 entities in total)
• 機能のキーワード: protease, peptidase, inhibitor, alpha-ketoamide, hydrolase, membrane, thiol protease
• 由来する生物種: Rattus norvegicus (Rat)
• 細胞内の位置: Cytoplasm : P97571
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 39729.90

構造登録者

Qian, J.,Campbell, R.L.,Davies, P.L. (登録日: 2007-09-12, 公開日: 2008-08-26, 最終更新日: 2023-08-30)

主引用文献

Qian, J.,Cuerrier, D.,Davies, P.L.,Li, Z.,Powers, J.C.,Campbell, R.L.
Cocrystal structures of primed side-extending alpha-ketoamide inhibitors reveal novel calpain-inhibitor aromatic interactions.
J.Med.Chem., 51:5264-5270, 2008

PubMed 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.

PubMed: 18702462
DOI: 10.1021/jm800045t

実験手法

X-RAY DIFFRACTION (1.8 Å)