View source for 4wq3


==Human calpain PEF(S) with (2Z,2Z')-2,2'-disulfanediylbis(3-(6-bromoindol-3-yl)acrylic acid) bound==
<StructureSection load='4wq3' size='340' side='right'caption='[[4wq3]], [[Resolution|resolution]] 1.79&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4wq3]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4WQ3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4WQ3 FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.79&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=3SU:(2Z)-3-(6-BROMO-1H-INDOL-3-YL)-2-SULFANYLPROP-2-ENOIC+ACID'>3SU</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4wq3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4wq3 OCA], [https://pdbe.org/4wq3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4wq3 RCSB], [https://www.ebi.ac.uk/pdbsum/4wq3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4wq3 ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/CPNS1_HUMAN 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.
<div style="background-color:#fffaf0;">
== 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<ref>PMID:28757975</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4wq3" style="background-color:#fffaf0;"></div>

==See Also==
*[[Calpain 3D structures|Calpain 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Adams SE]]
[[Category: Allemann RK]]
[[Category: Hallett MB]]
[[Category: Miller DJ]]
[[Category: Rizkallah PJ]]
[[Category: Robinson EJ]]