4C39

Structure of rat neuronal nitric oxide synthase heme domain in complex with 6-((((3S, 5R)-5-(((6-amino-4-methylpyridin-2-yl)methoxy) methyl)pyrrolidin-3-yl)oxy)methyl)-4-methylpyridin-2-amine

4C39 の概要

• エントリーDOI: 10.2210/pdb4c39/pdb
• 関連するPDBエントリー: 4C3A
• 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 (By similarity): P29476
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 100238.92

構造登録者

Li, H.,Poulos, T.L. (登録日: 2013-08-22, 公開日: 2014-04-02, 最終更新日: 2024-05-08)

主引用文献

Jing, Q.,Li, H.,Roman, L.J.,Martasek, P.,Poulos, T.L.,Silverman, R.B.
An Accessible Chiral Linker to Enhance Potency and Selectivity of Neuronal Nitric Oxide Synthase Inhibitors.
Acs Med.Chem.Lett., 5:56-, 2014

PubMed Abstract: The three important mammalian isozymes of nitric oxide synthase (NOS) are neuronal NOS (nNOS), endothelial NOS (eNOS), and inducible NOS (iNOS). Inhibitors of nNOS show promise as treatments for neurodegenerative diseases. Eight easily-synthesized compounds containing either one () or two () 2-amino-4-methylpyridine groups with a chiral pyrrolidine linker were designed as selective nNOS inhibitors. Inhibitor is the best of these compounds, having a potency of 9.7 nM and dual selectivity of 693 and 295 against eNOS and iNOS, respectively. Crystal structures of nNOS complexed with either or show a double-headed binding mode, where each 2-aminopyridine head group interacts with either a nNOS active site Glu residue or a heme propionate. In addition, the pyrrolidine nitrogen of contributes additional hydrogen bonds to the heme propionate, resulting in a unique binding orientation. In contrast, the lack of hydrogen bonds from the pyrrolidine of to the heme propionate allows the inhibitor to adopt two different binding orientations. Both and bind to eNOS in a single-headed mode, which is the structural basis for the isozyme selectivity.

PubMed: 24660051
DOI: 10.1021/ML400381S

実験手法

X-RAY DIFFRACTION (1.98 Å)