1mmw

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Rat neuronal NOS heme domain with vinyl-L-NIO bound

Overview

Isoform-specific nitric-oxide synthase (NOS) inhibitors may prove, clinically useful in reducing the pathophysiological effects associated, with increased neuronal NOS (nNOS) or inducible NOS (iNOS) activity in a, variety of neurological and inflammatory disorders. Analogs of the NOS, substrate L-arginine are pharmacologically attractive inhibitors because, of their stability, reliable cell uptake, and good selectivity for NOS, over other heme proteins. Some inhibitory arginine analogs show, significant isoform selectivity although the structural or mechanistic, basis of such selectivity is generally poorly understood. In the present, studies, we determined by x-ray crystallography the binding interactions, between rat nNOS and N5-(1-imino-3-butenyl)-L-ornithine (L-VNIO), a, previously identified mechanism-based, irreversible inactivator with, moderate nNOS selectivity. We have also synthesized and mechanistically, characterized several L-VNIO analogs and find, surprisingly, that even, relatively minor structural changes produce inhibitors that are either, iNOS-selective or non-selective. Furthermore, derivatives having a methyl, group added to the butenyl moiety of L-VNIO and L-VNIO derivatives that, are analogs of homoarginine rather than arginine display slow-on, slow-off, kinetics rather than irreversible inactivation. These results elucidate, some of the structural requirements for isoform-selective inhibition by, L-VNIO and its related alkyl- and alkenyl-imino ornithine and lysine, derivatives and may provide information useful in the ongoing rational, design of isoform-selective inhibitors.

About this Structure

1MMW is a Single protein structure of sequence from Rattus norvegicus with ACT, ZN, HEM, H4B and VIO as ligands. Active as Nitric-oxide synthase, with EC number 1.14.13.39 Full crystallographic information is available from OCA.

Reference

Structural characterization and kinetics of nitric-oxide synthase inhibition by novel N5-(iminoalkyl)- and N5-(iminoalkenyl)-ornithines., Bretscher LE, Li H, Poulos TL, Griffith OW, J Biol Chem. 2003 Nov 21;278(47):46789-97. Epub 2003 Sep 5. PMID:12960153

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