4CTY
Structure of bovine endothelial nitric oxide synthase heme domain in complex with (R)-6-(2-Amino-2-(3-(2-(6-amino-4-methylpyridin-2-yl) ethyl)phenyl)ethyl)-4-methylpyridin-2-amine
Summary for 4CTY
| Entry DOI | 10.2210/pdb4cty/pdb |
| Related | 4CTP 4CTQ 4CTR 4CTT 4CTU 4CTV 4CTW 4CTX 4CTZ 4CU0 4CU1 |
| Descriptor | NITRIC OXIDE SYNTHASE, ENDOTHELIAL, PROTOPORPHYRIN IX CONTAINING FE, 5,6,7,8-TETRAHYDROBIOPTERIN, ... (8 entities in total) |
| Functional Keywords | oxidoreductase, inhibitor complex |
| Biological source | BOS TAURUS (CATTLE) |
| Cellular location | Cell membrane: P29473 |
| Total number of polymer chains | 2 |
| Total formula weight | 102352.24 |
| Authors | Chreifi, G.,Li, H.,Poulos, T.L. (deposition date: 2014-03-15, release date: 2014-05-07, Last modification date: 2024-10-09) |
| Primary citation | Kang, S.,Tang, W.,Li, H.,Chreifi, G.,Martasek, P.,Roman, L.J.,Poulos, T.L.,Silverman, R.B. Nitric Oxide Synthase Inhibitors that Interact with Both a Heme Propionate and Tetrahydrobiopterin Show High Isoform Selectivity. J.Med.Chem., 57:4382-, 2014 Cited by PubMed Abstract: Overproduction of NO by nNOS is implicated in the pathogenesis of diverse neuronal disorders. Since NO signaling is involved in diverse physiological functions, selective inhibition of nNOS over other isoforms is essential to minimize side effects. A series of α-amino functionalized aminopyridine derivatives (3-8) were designed to probe the structure-activity relationship between ligand, heme propionate, and H4B. Compound 8R was identified as the most potent and selective molecule of this study, exhibiting a Ki of 24 nM for nNOS, with 273-fold and 2822-fold selectivity against iNOS and eNOS, respectively. Although crystal structures of 8R complexed with nNOS and eNOS revealed a similar binding mode, the selectivity stems from the distinct electrostatic environments in two isoforms that result in much lower inhibitor binding free energy in nNOS than in eNOS. These findings provide a basis for further development of simple, but even more selective and potent, nNOS inhibitors. PubMed: 24758147DOI: 10.1021/JM5004182 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.3 Å) |
Structure validation
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