4hze

Crystal structure of human Arginase-2 complexed with inhibitor 9

spinqualitylabelsall models 4hze, resolution 1.60Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4hze is a 3 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: BEN, BME, MN, X7A Related: 1d3v, 1pq3, 4hww, 4hxq Gene: ARG2 (Homo sapiens) Activity: Arginase, with EC number 3.5.3.1 Resources: FirstGlance, OCA, RCSB, PDBsum Function [ARGI2_HUMAN] May play a role in the regulation of extra-urea cycle arginine metabolism and also in down-regulation of nitric oxide synthesis. Extrahepatic arginase functions to regulate L-arginine bioavailability to NO synthase. Since NO synthase is found in the penile corpus cavernosum smooth muscle, the clitoral corpus cavernosum and the vagina, arginase II plays a role in both male and female sexual arousal. It is therefore a potential target for the treatment of male and female sexual arousal disorders. 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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