1zvi

From Proteopedia

proteopedia linkproteopedia link

spinqualitylabelsall models 1zvi, resolution 2.0Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

Rat Neuronal Nitric Oxide Synthase Oxygenase Domain

Overview

Nitric oxide synthesized from l-arginine by nitric oxide synthase isoforms, (NOS-I-III) is physiologically important but also can be deleterious when, overproduced. Selective NOS inhibitors are of clinical interest, given, their differing pathophysiological roles. Here we describe our approach to, target the unique NOS (6R,1'R,2'S)-5,6,7,8-tetrahydrobiopterin (H(4)Bip), binding site. By a combination of ligand- and structure-based design, the, structure-activity relationship (SAR) for a focused set of 41 pteridine, analogues on four scaffolds was developed, revealing selective NOS-I, inhibitors. The X-ray crystal structure of rat NOS-I dimeric-oxygenase, domain with H(4)Bip and l-arginine was determined and used for human, isoform homology modeling. All available NOS structural information was, subjected to comparative analysis of favorable protein-ligand interactions, using the GRID/concensus principal component analysis (CPCA) approach to, identify the isoform-specific interaction site. Our interpretation, based, on protein structures, is in good agreement with the ligand SAR and thus, permits the rational design of next-generation inhibitors targeting the, H(4)Bip binding site with enhanced isoform selectivity for therapeutics in, pathology with NO overproduction.

About this Structure

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

Reference

Structural analysis of isoform-specific inhibitors targeting the tetrahydrobiopterin binding site of human nitric oxide synthases., Matter H, Kumar HS, Fedorov R, Frey A, Kotsonis P, Hartmann E, Frohlich LG, Reif A, Pfleiderer W, Scheurer P, Ghosh DK, Schlichting I, Schmidt HH, J Med Chem. 2005 Jul 28;48(15):4783-92. PMID:16033258

Page seeded by OCA on Wed Nov 21 07:41:18 2007