4K5D

Structure of neuronal nitric oxide synthase heme domain in complex with (S)-1,2-bis((2-amino-4-methylpyridin-6-yl)-methoxy)-propan-3-amine

4K5D の概要

• エントリーDOI: 10.2210/pdb4k5d/pdb
• 関連するPDBエントリー: 4K5E 4K5F 4K5G 4K5H 4K5I 4K5J 4K5K
• 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: nitric oxide synthase, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• 由来する生物種: Rattus norvegicus (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: 100186.85

構造登録者

Li, H.,Poulos, T.L. (登録日: 2013-04-14, 公開日: 2013-09-18, 最終更新日: 2023-09-20)

主引用文献

Jing, Q.,Li, H.,Chreifi, G.,Roman, L.J.,Martasek, P.,Poulos, T.L.,Silverman, R.B.
Chiral linkers to improve selectivity of double-headed neuronal nitric oxide synthase inhibitors.
Bioorg.Med.Chem.Lett., 23:5674-5679, 2013

PubMed Abstract: To develop potent and selective nNOS inhibitors, new double-headed molecules with chiral linkers that derive from natural amino acids or their derivatives have been designed. The new structures contain two ether bonds, which greatly simplifies the synthesis and accelerates structure optimization. Inhibitor (R)-6b exhibits a potency of 32nM against nNOS and is 475 and 244 more selective for nNOS over eNOS and iNOS, respectively. Crystal structures show that the additional binding between the aminomethyl moiety of 6b and the two heme propionates in nNOS, but not eNOS, is the structural basis for its high selectivity. This work demonstrates the importance of stereochemistry in this class of molecules, which significantly influences the potency and selectivity of the inhibitors. The structure-activity information gathered here provides a guide for future structure optimization.

PubMed: 23993333
DOI: 10.1016/j.bmcl.2013.08.034

実験手法

X-RAY DIFFRACTION (2.096 Å)