4CTR

Structure of rat neuronal nitric oxide synthase heme domain in complex with 2-(6-Amino-4-methylpyridin-2-yl)-1-(3-(2-(6-amino-4- methylpyridin-2-yl)ethyl )phenyl)ethan-1-ol

4CTR の概要

• エントリーDOI: 10.2210/pdb4ctr/pdb
• 関連するPDBエントリー: 4CTP 4CTQ 4CTT 4CTU 4CTV 4CTW 4CTX 4CTY 4CTZ 4CU0 4CU1
• 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: 100248.96

構造登録者

Li, H.,Poulos, T.L. (登録日: 2014-03-15, 公開日: 2014-05-07, 最終更新日: 2024-05-08)

主引用文献

Kang, S.,Tang, W.,Li, H.,Chreifi, G.,Martasek, P.,Roman, L.J.,Poulos, T.L.,Silverman, R.B.
Nitric Oxide Synthase Inhibitors that Interact with Both a Heme Propionate and Tetrahydrobiopterin Show High Isoform Selectivity.
J.Med.Chem., 57:4382-, 2014

PubMed Abstract: Overproduction of NO by nNOS is implicated in the pathogenesis of diverse neuronal disorders. Since NO signaling is involved in diverse physiological functions, selective inhibition of nNOS over other isoforms is essential to minimize side effects. A series of α-amino functionalized aminopyridine derivatives (3-8) were designed to probe the structure-activity relationship between ligand, heme propionate, and H4B. Compound 8R was identified as the most potent and selective molecule of this study, exhibiting a Ki of 24 nM for nNOS, with 273-fold and 2822-fold selectivity against iNOS and eNOS, respectively. Although crystal structures of 8R complexed with nNOS and eNOS revealed a similar binding mode, the selectivity stems from the distinct electrostatic environments in two isoforms that result in much lower inhibitor binding free energy in nNOS than in eNOS. These findings provide a basis for further development of simple, but even more selective and potent, nNOS inhibitors.

PubMed: 24758147
DOI: 10.1021/JM5004182

実験手法

X-RAY DIFFRACTION (2.2 Å)