4WQ3

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

Summary for 4WQ3

• Entry DOI: 10.2210/pdb4wq3/pdb
• Descriptor: Calpain small subunit 1, CALCIUM ION, (2Z)-3-(6-bromo-1H-indol-3-yl)-2-sulfanylprop-2-enoic acid, ... (4 entities in total)
• Functional Keywords: pef(s), domain vi, calcium binding domain, cysteine protease, mercaptoacrylic acid, hydrolase
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm : P04632
• Total number of polymer chains: 2
• Total formula weight: 41546.46

Authors

Adams, S.E.,Robinson, E.J.,Rizkallah, P.J.,Miller, D.J.,Hallett, M.B.,Allemann, R.K. (deposition date: 2014-10-21, release date: 2015-09-02, Last modification date: 2024-01-10)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.79 Å)