Structure of rat neuronal nitric oxide synthase heme domain complexed with 6-(((3S,4S)-4-(2-(3-Fluorophenethylamino)ethoxy)pyrrolidin-3-yl)methyl)pyridin-2-amine
3nnz is a 2 chain structure with sequence from Buffalo rat. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
[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.
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Selective inhibition of the neuronal isoform of nitric oxide synthase (nNOS) over endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase (iNOS) has become a promising strategy for the discovery of new therapeutic agents for neurodegenerative diseases. However, because of the high sequence homology of different isozymes in the substrate binding pocket, developing inhibitors with both potency and excellent isoform selectivity remains a challenging problem. Herein, we report the evaluation of a recently discovered peripheral hydrophobic pocket (Tyr(706), Leu(337), and Met(336)) that opens up upon inhibitor binding and its potential in designing potent and selective nNOS inhibitors using three compounds, 2a, 2b, and 3. Crystal structure results show that inhibitors 2a and 3 adopted the same binding mode as lead compound 1. We also found that hydrophobic interactions between the 4-methyl group of the aminopyridine ring of these compounds with the side chain of Met(336), as well as the pi-pi stacking interaction between the pyridinyl motif and the side chain of Tyr(706) are important for the high potency and selectivity of these nNOS inhibitors.
Peripheral but crucial: A hydrophobic pocket (Tyr706, Leu(337), and Met(336)) for potent and selective inhibition of neuronal nitric oxide synthase.,Xue F, Li H, Fang J, Roman LJ, Martasek P, Poulos TL, Silverman RB Bioorg Med Chem Lett. 2010 Aug 26. PMID:20833542[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
↑Xue F, Li H, Fang J, Roman LJ, Martasek P, Poulos TL, Silverman RB. Peripheral but crucial: A hydrophobic pocket (Tyr706, Leu(337), and Met(336)) for potent and selective inhibition of neuronal nitric oxide synthase. Bioorg Med Chem Lett. 2010 Aug 26. PMID:20833542 doi:10.1016/j.bmcl.2010.08.096
