3JWZ

Structure of endothelial nitric oxide synthase heme domain complexed with N1-[(3' S,4' R)-4'-((6"-amino-4"-methylpyridin-2"-yl)methyl)pyrrolidin-3'-yl]-N2-(3'-fluorophenethyl)ethane-1,2-diamine tetrahydrochloride

3JWZ の概要

• エントリーDOI: 10.2210/pdb3jwz/pdb
• 関連するPDBエントリー: 3JW0 3JW1 3JW2 3JW3 3JW4 3JW5 3JW6 3JWS 3JWT 3JWU 3JWV 3JWW 3JWX 3JWY
• 分子名称: Nitric oxide synthase, endothelial, PROTOPORPHYRIN IX CONTAINING FE, 5,6,7,8-TETRAHYDROBIOPTERIN, ... (9 entities in total)
• 機能のキーワード: heme enzyme, substrate inhibitor, oxidoreductase
• 由来する生物種: Bos taurus (bovine)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 102522.35

構造登録者

Delker, S.L.,Li, H.,Poulos, T.L. (登録日: 2009-09-18, 公開日: 2010-05-05, 最終更新日: 2024-02-21)

主引用文献

Delker, S.L.,Ji, H.,Li, H.,Jamal, J.,Fang, J.,Xue, F.,Silverman, R.B.,Poulos, T.L.
Unexpected binding modes of nitric oxide synthase inhibitors effective in the prevention of a cerebral palsy phenotype in an animal model.
J.Am.Chem.Soc., 132:5437-5442, 2010

PubMed Abstract: Selective inhibition of the neuronal isoform of nitric oxide synthase NOS (nNOS) has been shown to prevent brain injury and is important for the treatment of various neurodegenerative disorders. However, given the high active site conservation among all three NOS isoforms, the design of selective inhibitors is an extremely challenging problem. Here we present the structural basis for why novel and potent nNOS inhibitors exhibit the highest level of selectivity over eNOS reported so far (approximately 3,800-fold). By using a combination of crystallography, computational methods, and site-directed mutagenesis, we found that inhibitor chirality and an unanticipated structural change of the target enzyme control both the orientation and selectivity of these novel nNOS inhibitors. A new hot spot generated as a result of enzyme elasticity provides important information for the future fragment-based design of selective NOS inhibitors.

PubMed: 20337441
DOI: 10.1021/ja910228a

実験手法

X-RAY DIFFRACTION (2.4 Å)