View source for 4hww


==Crystal structure of human Arginase-1 complexed with inhibitor 9==
<StructureSection load='4hww' size='340' side='right'caption='[[4hww]], [[Resolution|resolution]] 1.30&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4hww]] 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=4HWW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4HWW 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]] 1.298&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene>, <scene name='pdbligand=X7A:[(5R)-5-AMINO-5-CARBOXY-7-(PIPERIDIN-1-YL)HEPTYL](TRIHYDROXY)BORATE(1-)'>X7A</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=4hww FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4hww OCA], [https://pdbe.org/4hww PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4hww RCSB], [https://www.ebi.ac.uk/pdbsum/4hww PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4hww ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/ARGI1_HUMAN ARGI1_HUMAN] Defects in ARG1 are the cause of argininemia (ARGIN) [MIM:[https://omim.org/entry/207800 207800]; also known as hyperargininemia. Argininemia is a rare autosomal recessive disorder of the urea cycle. Arginine is elevated in the blood and cerebrospinal fluid, and periodic hyperammonemia occurs. Clinical manifestations include developmental delay, seizures, mental retardation, hypotonia, ataxia, progressive spastic quadriplegia.<ref>PMID:1463019</ref> <ref>PMID:7649538</ref> 
== Function ==
[https://www.uniprot.org/uniprot/ARGI1_HUMAN ARGI1_HUMAN] 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Recent efforts to identify treatments for myocardial ischemia reperfusion injury have resulted in the discovery of a novel series of highly potent alpha,alpha-disubstituted amino acid-based arginase inhibitors. The lead candidate, (R)-2-amino-6-borono-2-(2-(piperidin-1-yl)ethyl)hexanoic acid, compound 9, inhibits human arginases I and II with IC50s of 223 and 509 nM, respectively, and is active in a recombinant cellular assay overexpressing human arginase I (CHO cells). It is 28% orally bioavailable and significantly reduces the infarct size in a rat model of myocardial ischemia/reperfusion injury. Herein, we report the design, synthesis, and structure-activity relationships (SAR) for this novel series of inhibitors along with pharmacokinetic and in vivo efficacy data for compound 9 and X-ray crystallography data for selected lead compounds cocrystallized with arginases I and II.

Discovery of (R)-2-Amino-6-borono-2-(2-(piperidin-1-yl)ethyl)hexanoic Acid and Congeners As Highly Potent Inhibitors of Human Arginases I and II for Treatment of Myocardial Reperfusion Injury.,Van Zandt MC, Whitehouse DL, Golebiowski A, Ji MK, Zhang M, Beckett RP, Jagdmann GE, Ryder TR, Sheeler R, Andreoli M, Conway B, Mahboubi K, D'Angelo G, Mitschler A, Cousido-Siah A, Ruiz FX, Howard EI, Podjarny AD, Schroeter H J Med Chem. 2013 Mar 28;56(6):2568-80. doi: 10.1021/jm400014c. Epub 2013 Mar 8. PMID:23472952<ref>PMID:23472952</ref>

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

==See Also==
*[[Arginase 3D structures|Arginase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Andreoli M]]
[[Category: Beckett P]]
[[Category: Conway B]]
[[Category: Cousido-Siah A]]
[[Category: Golebiowski A]]
[[Category: Ji M]]
[[Category: Mahboubi K]]
[[Category: Mitschler A]]
[[Category: Podjarny A]]
[[Category: Ruiz FX]]
[[Category: Schroeter H]]
[[Category: Sheeler R]]
[[Category: Van Zandt MC]]
[[Category: Whitehouse DL]]
[[Category: Zhang M]]