3nlk

From Proteopedia

Structure of neuronal nitric oxide synthase R349A mutant heme domain in complex with 6-{{(3'S,4'S)-3'-[2"-(3-fluorophenethylamino)ethoxy]pyrrolidin-4'-yl}methyl}-4-methylpyridin-2-amine

PDB ID 3nlk

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Structural highlights

3nlk is a 2 chain structure with sequence from Rattus norvegicus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.02Å
Ligands:	, , , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

NOS1_RAT Produces nitric oxide (NO) which is a messenger molecule with diverse functions throughout the body. In the brain and peripheral nervous system, NO displays many properties of a neurotransmitter. Inhibitory transmitter for non-adrenergic and non-cholinergic nerves in the colorectum. Probably has nitrosylase activity and mediates cysteine S-nitrosylation of cytoplasmic target proteins such SRR. Inhibitory transmitter for non-adrenergic and non-cholinergic nerves in the colorectum.

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