4upq | pdb_00004upq

Structure of bovine endothelial nitric oxide synthase heme domain in complex with N',N'-{[(2R)-3-aminopropane-1,2-diyl]bis(oxymethanediylbenzene-3,1-diyl)}dithiophene-2-carboximidamide

spinqualitylabelsall models 4upq, resolution 2.03Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4upq 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 2.03Å Ligands: ACT, CAS, GOL, H4B, HEM, I5U, 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 To develop potent and selective nNOS inhibitors, a new series of double-headed molecules with chiral linkers that derive from natural amino acid derivatives have been designed and synthesized. The new structures integrate a thiophenecarboximidamide head with two types of chiral linkers, presenting easy synthesis and good inhibitory properties. Inhibitor (S)-9b exhibits a potency of 14.7nM against nNOS and is 1134 and 322-fold more selective for nNOS over eNOS and iNOS, respectively. Crystal structures show that the additional binding between the aminomethyl moiety of 9b and propionate A on the heme and tetrahydrobiopterin (H4B) in nNOS, but not eNOS, contributes to its high selectivity. This work demonstrates the advantage of integrating known structures into structure optimization, and it should be possible to more readily develop compounds that incorporate bioavailability with these advanced features. Moreover, this integrative strategy is a general approach in new drug discovery. Combination of chiral linkers with thiophenecarboximidamide heads to improve the selectivity of inhibitors of neuronal nitric oxide synthase.,Jing Q, Li H, Roman LJ, Martasek P, Poulos TL, Silverman RB Bioorg Med Chem Lett. 2014 Aug 12. pii: S0960-894X(14)00814-2. doi:, 10.1016/j.bmcl.2014.07.079. PMID:25149509 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Nitric Oxide Synthase 3D structures

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