4CX5

Structure of rat neuronal nitric oxide synthase H341L mutant heme domain in complex with 4-METHYL-6-(((3R,4R)-4-((5-(PYRIDIN-2-YL) PENTYL)OXY)PYRROLIDIN-3-YL)METHYL)PYRIDIN-2-AMINE

4CX5 の概要

• エントリーDOI: 10.2210/pdb4cx5/pdb
• 関連するPDBエントリー: 4CWV 4CWW 4CWX 4CWY 4CWZ 4CX0 4CX1 4CX2 4CX3 4CX4 4CX6 4CX7
• 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: 100183.01

構造登録者

Li, H.,Poulos, T.L. (登録日: 2014-04-03, 公開日: 2014-08-13, 最終更新日: 2024-05-08)

主引用文献

Li, H.,Jamal, J.,Delker, S.L.,Plaza, C.,Ji, H.,Jing, Q.,Huang, H.,Kang, S.,Silverman, R.B.,Poulos, T.L.
Mobility of a Conserved Tyrosine Residue Controls Isoform-Dependent Enzyme-Inhibitor Interactions in Nitric Oxide Synthases.
Biochemistry, 53:5272-, 2014

PubMed Abstract: Many pyrrolidine-based inhibitors highly selective for neuronal nitric oxide synthase (nNOS) over endothelial NOS (eNOS) exhibit dramatically different binding modes. In some cases, the inhibitor binds in a 180° flipped orientation in nNOS relative to eNOS. From the several crystal structures we have determined, we know that isoform selectivity correlates with the rotamer position of a conserved tyrosine residue that H-bonds with a heme propionate. In nNOS, this Tyr more readily adopts the out-rotamer conformation, while in eNOS, the Tyr tends to remain fixed in the original in-rotamer conformation. In the out-rotamer conformation, inhibitors are able to form better H-bonds with the protein and heme, thus increasing inhibitor potency. A segment of polypeptide that runs along the surface near the conserved Tyr has long been thought to be the reason for the difference in Tyr mobility. Although this segment is usually disordered in both eNOS and nNOS, sequence comparisons and modeling from a few structures show that this segment is structured quite differently in eNOS and nNOS. In this study, we have probed the importance of this surface segment near the Tyr by making a few mutants in the region followed by crystal structure determinations. In addition, because the segment near the conserved Tyr is highly ordered in iNOS, we also determined the structure of an iNOS-inhibitor complex. This new structure provides further insight into the critical role that mobility plays in isoform selectivity.

PubMed: 25089924
DOI: 10.1021/BI500561H

実験手法

X-RAY DIFFRACTION (1.8 Å)