1ZVI

Rat Neuronal Nitric Oxide Synthase Oxygenase Domain

1ZVI の概要

• エントリーDOI: 10.2210/pdb1zvi/pdb
• 関連するPDBエントリー: 1N2N 1QW4 1QW5 1QW6 1QWC 1VAG 1ZVL
• 分子名称: Nitric-oxide synthase, brain, ZINC ION, PROTOPORPHYRIN IX CONTAINING FE, ... (5 entities in total)
• 機能のキーワード: rat nnosoxy, targeting tetrahydrobiopterin binding site, oxidoreductase
• 由来する生物種: Rattus norvegicus (Norway rat)
• 細胞内の位置: Cell membrane, sarcolemma ; Peripheral membrane protein : P29476
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 49503.35

構造登録者

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. (登録日: 2005-06-02, 公開日: 2005-08-02, 最終更新日: 2024-02-14)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2 Å)