5AGO

Structure of rat neuronal nitric oxide synthase heme domain in complex with (S)-2-Amino-5-(2-mercaptoacetimidamido)pentanoic acid

5AGO の概要

• エントリーDOI: 10.2210/pdb5ago/pdb
• 関連するPDBエントリー: 5AGK 5AGL 5AGM 5AGN 5AGP
• 分子名称: NITRIC OXIDE SYNTHASE, BRAIN, PROTOPORPHYRIN IX CONTAINING FE, 5,6,7,8-TETRAHYDROBIOPTERIN, ... (7 entities in total)
• 機能のキーワード: oxidoreductase, inhibitor complex
• 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: 2
• 化学式量合計: 99934.58

構造登録者

Li, H.,Poulos, T.L. (登録日: 2015-02-02, 公開日: 2015-04-29, 最終更新日: 2024-05-08)

主引用文献

Tang, W.,Li, H.,Doud, E.H.,Chen, Y.,Choing, S.,Plaza, C.,Kelleher, N.L.,Poulos, T.L.,Silverman, R.B.
Mechanism of Inactivation of Neuronal Nitric Oxide Synthase by (S)-2-Amino-5-(2-(Methylthio)Acetimidamido)Pentanoic Acid.
J.Am.Chem.Soc., 137:5980-, 2015

PubMed Abstract: Nitric oxide synthase (NOS) catalyzes the conversion of l-arginine to l-citrulline and the second messenger nitric oxide. Three mechanistic pathways are proposed for the inactivation of neuronal NOS (nNOS) by (S)-2-amino-5-(2-(methylthio)acetimidamido)pentanoic acid (1): sulfide oxidation, oxidative dethiolation, and oxidative demethylation. Four possible intermediates were synthesized. All compounds were assayed with nNOS, their IC50, KI, and kinact values were obtained, and their crystal structures were determined. The identification and characterization of the products formed during inactivation provide evidence for the details of the inactivation mechanism. On the basis of these studies, the most probable mechanism for the inactivation of nNOS involves oxidative demethylation with the resulting thiol coordinating to the cofactor heme iron. Although nNOS is a heme-containing enzyme, this is the first example of a NOS that catalyzes an S-demethylation reaction; the novel mechanism of inactivation described here could be applied to the design of inactivators of other heme-dependent enzymes.

PubMed: 25874809
DOI: 10.1021/JACS.5B01202

実験手法

X-RAY DIFFRACTION (1.902 Å)