4HZE
Crystal structure of human Arginase-2 complexed with inhibitor 9
Summary for 4HZE
| Entry DOI | 10.2210/pdb4hze/pdb |
| Related | 1D3V 1PQ3 4HWW 4HXQ |
| Descriptor | Arginase-2, mitochondrial, MANGANESE (II) ION, BENZAMIDINE, ... (6 entities in total) |
| Functional Keywords | metalloenzyme, alpha/beta fold, hydrolase, arginine metabolism, manganese, mitochondrion, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor |
| Biological source | Homo sapiens (human) |
| Cellular location | Mitochondrion : P78540 |
| Total number of polymer chains | 3 |
| Total formula weight | 101763.40 |
| Authors | Cousido-Siah, A.,Mitschler, A.,Ruiz, F.X.,Whitehouse, D.L.,Golebiowski, A.,Ji, M.,Zhang, M.,Beckett, P.,Sheeler, R.,Andreoli, M.,Conway, B.,Mahboubi, K.,Schroeter, H.,Van Zandt, M.C.,Podjarny, A. (deposition date: 2012-11-15, release date: 2013-03-20, Last modification date: 2023-09-20) |
| Primary citation | Van Zandt, M.C.,Whitehouse, D.L.,Golebiowski, A.,Ji, M.K.,Zhang, M.,Beckett, R.P.,Jagdmann, G.E.,Ryder, T.R.,Sheeler, R.,Andreoli, M.,Conway, B.,Mahboubi, K.,D'Angelo, G.,Mitschler, A.,Cousido-Siah, A.,Ruiz, F.X.,Howard, E.I.,Podjarny, A.D.,Schroeter, H. 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. J.Med.Chem., 56:2568-2580, 2013 Cited by PubMed Abstract: Recent efforts to identify treatments for myocardial ischemia reperfusion injury have resulted in the discovery of a novel series of highly potent α,α-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. PubMed: 23472952DOI: 10.1021/jm400014c PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.602 Å) |
Structure validation
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