4uha

Structure of bovine endothelial nitric oxide synthase heme domain in complex with 3-(2-(6-Amino-4-methylpyridin-2-yl)ethyl)-5-(methyl(2-(methylamino)ethyl)amino)benzonitrile

spinqualitylabelsall models 4uha, resolution 2.20Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4uha is a 2 chain structure with sequence from Bos taurus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.2Å Ligands: ACT, CAS, GOL, H4B, HEM, Q1T, ZN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function NOS3_BOVIN Produces nitric oxide (NO) which is implicated in vascular smooth muscle relaxation through a cGMP-mediated signal transduction pathway. NO mediates vascular endothelial growth factor (VEGF)-induced angiogenesis in coronary vessels and promotes blood clotting through the activation of platelets. Publication Abstract from PubMed We have analyzed a recently obtained crystal structure of human neuronal nitric oxide synthase (nNOS) and then designed and synthesized several 2-aminopyridine derivatives containing a truncated side chain to avoid the hydrophobic pocket that differentiates human and rat nNOS in an attempt to explore alternative binding poses along the substrate access channel of human nNOS. Introduction of an N-methylethane-1,2-diamine side chain and conformational constraints such as benzonitrile and pyridine as the middle aromatic linker were sufficient to increase human and rat nNOS binding affinity and inducible and endothelial NOS selectivity. We found that 14b is a potent inhibitor; the binding modes with human and rat nNOS are unexpected, inducing side chain rotamer changes in Gln478 (rat) at the top of the active site. Compound 19c exhibits Ki values of 24 and 55 nM for rat and human nNOS, respectively, with 153-fold iNOS and 1040-fold eNOS selectivity. 19c has 18% oral bioavailability. 2-Aminopyridines with a Truncated Side Chain To Improve Human Neuronal Nitric Oxide Synthase Inhibitory Potency and Selectivity.,Kang S, Li H, Tang W, Martasek P, Roman LJ, Poulos TL, Silverman RB J Med Chem. 2015 Jul 10. PMID:26120733 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Nitric Oxide Synthase 3D structures

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