5d69

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

spinqualitylabelsall models 5d69, resolution 1.97Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5d69 is a 2 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 57T, CA, SO4 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [CPNS1_HUMAN] Regulatory subunit of the calcium-regulated non-lysosomal thiol-protease which catalyzes limited proteolysis of substrates involved in cytoskeletal remodeling and signal transduction. Publication Abstract from PubMed 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. alpha-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 alpha-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 alpha-mercaptoacrylic acids and X-ray crystallography revealed that the IC50 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 alpha-mercaptoacrylic acids. Conformationally restricted calpain inhibitors.,Adams SE, Robinson EJ, Miller DJ, Rizkallah PJ, Hallett MB, Allemann RK Chem Sci. 2015 Dec 1;6(12):6865-6871. doi: 10.1039/c5sc01158b. Epub 2015 Aug 24. PMID:28757975 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Calpain 3D structures

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