1ZVL

Rat Neuronal Nitric Oxide Synthase Oxygenase Domain complexed with natural substrate L-Arg.

Summary for 1ZVL

• Entry DOI: 10.2210/pdb1zvl/pdb
• Related: 1N2N 1QW4 1QW5 1QW6 1QWC 1VAG 1ZVI
• Descriptor: Nitric-oxide synthase, brain, ZINC ION, PROTOPORPHYRIN IX CONTAINING FE, ... (6 entities in total)
• Functional Keywords: rat nnosoxy, targeting tetrahydrobiopterin binding site., oxidoreductase
• Biological source: Rattus norvegicus (Norway rat)
• Cellular location: Cell membrane, sarcolemma ; Peripheral membrane protein : P29476
• Total number of polymer chains: 2
• Total formula weight: 99291.70

Authors

Matter, H.,Kumar, H.S.,Fedorov, R.,Frey, A.,Kotsonis, P.,Hartmann, E.,Frohlich, L.G.,Reif, A.,Pfleiderer, W.,Scheurer, P.,Ghosh, D.K.,Schlichting, I.,Schmidt, H.H. (deposition date: 2005-06-02, release date: 2005-08-02, Last modification date: 2024-02-14)

Primary citation

Matter, H.,Kumar, H.S.,Fedorov, R.,Frey, A.,Kotsonis, P.,Hartmann, E.,Frohlich, L.G.,Reif, A.,Pfleiderer, W.,Scheurer, P.,Ghosh, D.K.,Schlichting, I.,Schmidt, H.H.
Structural Analysis of Isoform-Specific Inhibitors Targeting the Tetrahydrobiopterin Binding Site of Human Nitric Oxide Synthases.
J.Med.Chem., 48:4783-4792, 2005

PubMed Abstract: 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.

PubMed: 16033258
DOI: 10.1021/jm050007x

Experimental method

X-RAY DIFFRACTION (2.5 Å)