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4phm

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The Structural Basis of Differential Inhibition of Human Calpain by Indole and Phenyl alpha-Mercaptoacrylic Acids

Structural highlights

4phm is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.03Å
Ligands:	,
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

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^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

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

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4phm"

@@ Line 4: / Line 4: @@
 == Structural highlights ==
 <table><tr><td colspan='2'>[[4phm]] 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=4PHM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4PHM FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=2UD:3-(5-BROMO-1H-INDOL-3-YL)-2-THIOXOPROPANOIC+ACID'>2UD</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.03&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=2UD:3-(5-BROMO-1H-INDOL-3-YL)-2-THIOXOPROPANOIC+ACID'>2UD</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=4phm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4phm OCA], [https://pdbe.org/4phm PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4phm RCSB], [https://www.ebi.ac.uk/pdbsum/4phm PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4phm ProSAT]</span></td></tr>
 </table>

4phm

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Current revision

The Structural Basis of Differential Inhibition of Human Calpain by Indole and Phenyl alpha-Mercaptoacrylic Acids

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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