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==The Structural Basis of Differential Inhibition of Human Calpain by Indole and Phenyl alpha-Mercaptoacrylic Acids. The complex with (Z)-3-(4-chlorophenyl)-2-mercaptoacrylic acid==
<StructureSection load='4phk' size='340' side='right'caption='[[4phk]], [[Resolution|resolution]] 2.05&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4phk]] 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=4PHK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4PHK 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]] 2.05&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=2UB:(Z)-3-(4-CHLOROPHENYL)-2-MERCAPTOACRYLIC+ACID'>2UB</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=4phk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4phk OCA], [https://pdbe.org/4phk PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4phk RCSB], [https://www.ebi.ac.uk/pdbsum/4phk PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4phk 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.
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== Publication Abstract from PubMed ==
Excessive activity of neutrophils has been linked to many pathological conditions, including rheumatoid arthritis, cancer and Alzheimer's disease. Calpain-I is a Ca2+-dependent protease that plays a key role in the extravasation of neutrophils from the blood stream prior to causing damage within affected tissues. Inhibition of calpain-I with small molecule mercaptoacrylic acid derivatives slows the cell spreading process of live neutrophils and so these compounds represent promising drug leads. Here we present the 2.05 and 2.03A co-crystal X-ray structures of the pentaEF hand region PEF(S) from human calpain with (Z)-3-(4-chlorophenyl)-2-mercaptoacrylic acid and (Z)-3-(5-bromoindol-3-yl)-2-mercaptoacrylic acid. In both structures, the alpha-mercaptoacrylic acid derivatives bind between two alpha-helices in a hydrophobic pocket that is also exploited by a leucine residue of the endogenous regulatory calpain inhibitor calpastatin. Hydrophobic interactions between the aromatic rings of both inhibitors and the aliphatic residues of the pocket are integral for tight binding. In the case of (Z)-3-(5-bromoindol-3-yl)-2-mercaptoacrylic acid, hydrogen bonds form between the mercaptoacrylic acid substituent lying outside the pocket and the protein and the carboxylate group is coplanar with the aromatic ring system. Multiple conformations of (Z)-3-(5-bromoindol-3-yl)-2-mercaptoacrylic acid were found within the pocket. The increased potency of (Z)-3-(5-bromoindol-3-yl)-2-mercaptoacrylic acid relative to (Z)-3-(4-chlorophenyl)-2-mercaptoacrylic acid may be a consequence of the indole group binding more deeply in the hydrophobic pocket of PEF(S) than the phenyl ring.

The structural basis of differential inhibition of human calpain by indole and phenyl alpha-mercaptoacrylic acids.,Adams SE, Rizkallah PJ, Miller DJ, Robinson EJ, Hallett MB, Allemann RK J Struct Biol. 2014 Jul 30. pii: S1047-8477(14)00162-2. doi:, 10.1016/j.jsb.2014.07.004. PMID:25086406<ref>PMID:25086406</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 4phk" 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 E]]