3nlg

Structure of endothelial nitric oxide synthase heme domain complexed with 6-{{(3'S,4'R)-3'-[2"-(3-fluorophenethylamino)ethoxy]pyrrolidin-4'-yl}methyl}-4-methylpyridin-2-amine

Structural highlights

3nlg is a 2 chain structure with sequence from Bovin. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, , , , , ,
Related:	3nld, 3nle, 3nlf, 3nlh, 3nli, 3nlj, 3nlk, 3nlm, 3nln, 3nlo, 3nlp, 3nlq, 3nlr, 3nlt, 3nlu, 3nlv, 3nlw, 3nlx, 3nly, 3nlz, 3nm0
Gene:	NOS3 (BOVIN)
Activity:	Nitric-oxide synthase (NADPH dependent), with EC number 1.14.13.39
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

Neuronal nitric oxide synthase (nNOS) represents an important therapeutic target for the prevention of brain injury and the treatment of various neurodegenerative disorders. A series of trans-substituted amino pyrrolidinomethyl 2-aminopyridine derivatives (8-34) was designed and synthesized. A structure-activity relationship analysis led to the discovery of low nanomolar nNOS inhibitors ((+/-)-32 and (+/-)-34) with more than 1000-fold selectivity for nNOS over eNOS. Four enantiomerically pure isomers of 3'-[2-(3-fluorophenethylamino)ethoxy]pyrrolidin-4'-yl}methyl}-4-methy lpyridin-2-amine (4) also were synthesized. It was found that (3'R,4'R)-4 can induce enzyme elasticity to generate a new "hot spot" for ligand binding. The inhibitor adopts a unique binding mode, the same as that observed for (3'R,4'R)-3'-[2-(3-fluorophenethylamino)ethylamino]pyrrolidin-4'-yl}m ethyl}-4-methylpyridin-2-amine ((3'R,4'R)-3) ( J. Am. Chem. Soc. 2010 , 132 ( 15 ), 5437 - 5442 ). On the basis of structure-activity relationships of 8-34 and different binding conformations of the cis and trans isomers of 3 and 4, critical structural requirements of the NOS active site for ligand binding are revealed.

Exploration of the Active Site of Neuronal Nitric Oxide Synthase by the Design and Synthesis of Pyrrolidinomethyl 2-Aminopyridine Derivatives.,Ji H, Delker SL, Li H, Martasek P, Roman LJ, Poulos TL, Silverman RB J Med Chem. 2010 Oct 19. PMID:20958055^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Ji H, Delker SL, Li H, Martasek P, Roman LJ, Poulos TL, Silverman RB. Exploration of the Active Site of Neuronal Nitric Oxide Synthase by the Design and Synthesis of Pyrrolidinomethyl 2-Aminopyridine Derivatives. J Med Chem. 2010 Oct 19. PMID:20958055 doi:10.1021/jm100947x

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OCA

[1] Ji H, Delker SL, Li H, Martasek P, Roman LJ, Poulos TL, Silverman RB. Exploration of the Active Site of Neuronal Nitric Oxide Synthase by the Design and Synthesis of Pyrrolidinomethyl 2-Aminopyridine Derivatives. J Med Chem. 2010 Oct 19. PMID:20958055 doi:10.1021/jm100947x

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