5D69

Human calpain PEF(S) with (2Z,2Z')-2,2'-disulfanediylbis(3-(6-iodoindol-3-yl)acrylic acid) bound

5D69 の概要

• エントリーDOI: 10.2210/pdb5d69/pdb
• 分子名称: Calpain small subunit 1, CALCIUM ION, (2E,2'Z)-2,2'-disulfanediylbis[3-(4-iodophenyl)prop-2-enoic acid], ... (5 entities in total)
• 機能のキーワード: pef(s), domain vi, calcium binding domain, cysteine protease, mercaptoacrylic acid, hydrolase
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Cytoplasm : P04632
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 41670.35

構造登録者

Adams, S.E.,Robinson, E.J.,Rizkallah, P.J.,Miller, D.J.,Hallett, M.B.,Allemann, R.K. (登録日: 2015-08-11, 公開日: 2015-09-02, 最終更新日: 2024-05-08)

主引用文献

Adams, S.E.,Robinson, E.J.,Miller, D.J.,Rizkallah, P.J.,Hallett, M.B.,Allemann, R.K.
Conformationally restricted calpain inhibitors.
Chem Sci, 6:6865-6871, 2015

PubMed Abstract: The cysteine protease calpain-I is linked to several diseases and is therefore a valuable target for inhibition. Selective inhibition of calpain-I has proved difficult as most compounds target the active site and inhibit a broad spectrum of cysteine proteases as well as other calpain isoforms. Selective inhibitors might not only be potential drugs but should act as tools to explore the physiological and pathophysiological roles of calpain-I. α-Mercaptoacrylic acid based calpain inhibitors are potent, cell permeable and selective inhibitors of calpain-I and calpain-II. These inhibitors target the calcium binding domain PEF(S) of calpain-I and -II. Here X-ray diffraction analysis of co-crystals of PEF(S) revealed that the disulfide form of an α-mercaptoacrylic acid bound within a hydrophobic groove that is also targeted by a calpastatin inhibitory region and made a greater number of favourable interactions with the protein than the reduced sulfhydryl form. Measurement of the inhibitory potency of the α-mercaptoacrylic acids and X-ray crystallography revealed that the IC values decreased significantly on oxidation as a consequence of the stereo-electronic properties of disulfide bonds that restrict rotation around the S-S bond. Consequently, thioether analogues inhibited calpain-I with potencies similar to those of the free sulfhydryl forms of α-mercaptoacrylic acids.

PubMed: 28757975
DOI: 10.1039/c5sc01158b

実験手法

X-RAY DIFFRACTION (1.97 Å)