1ZZT

Bovine eNOS N368D/V106M double mutant with L-N(omega)-Nitroarginine-(4R)-Amino-L-Proline Amide Bound

1ZZT の概要

• エントリーDOI: 10.2210/pdb1zzt/pdb
• 関連するPDBエントリー: 1P6N
• 分子名称: Nitric-oxide synthase, endothelial, ACETATE ION, ZINC ION, ... (7 entities in total)
• 機能のキーワード: enzyme-inhibtor complex, oxidoreductase
• 由来する生物種: Bos taurus (cattle)
• 細胞内の位置: Cell membrane: P29473
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 96541.77

構造登録者

Li, H.,Flinspach, M.L.,Igarashi, J.,Jamal, J.,Yang, W.,Gomez-Vidal, J.A.,Litzinger, E.A.,Silverman, R.B.,Poulos, T.L. (登録日: 2005-06-14, 公開日: 2005-12-06, 最終更新日: 2024-11-13)

主引用文献

Li, H.,Flinspach, M.L.,Igarashi, J.,Jamal, J.,Yang, W.,Litzinger, E.A.,Huang, H.,Erdal, E.P.,Silverman, R.B.,Poulos, T.L.
Exploring the Binding Conformations of Bulkier Dipeptide Amide Inhibitors in Constitutive Nitric Oxide Synthases.
Biochemistry, 44:15222-15229, 2005

PubMed Abstract: A series of L-nitroarginine-based dipeptide inhibitors are highly selective for neuronal nitric oxide synthase (nNOS) over the endothelial isoform (eNOS). Crystal structures of these dipeptides bound to both isoforms revealed two different conformations, curled in nNOS and extended in eNOS, corresponding to higher and lower binding affinity to the two isoforms, respectively. In previous studies we found that the primary reason for selectivity is that Asp597 in nNOS, which is Asn368 in eNOS, provides greater electrostatic stabilization in the inhibitor complex. While this is the case for smaller dipeptide inhibitors, electrostatic stabilization may no longer be the sole determinant for isoform selectivity with bulkier dipeptide inhibitors. Another residue farther away from the active site, Met336 in nNOS (Val106 in eNOS), is in contact with bulkier dipeptide inhibitors. Double mutants were made to exchange the D597/M336 pair in nNOS with N368/V106 in eNOS. Here we report crystal structures and inhibition constants for bulkier dipeptide inhibitors bound to nNOS and eNOS that illustrate the important role played by residues near the entry to the active site in isoform selective inhibition.

PubMed: 16285725
DOI: 10.1021/bi0513610

実験手法

X-RAY DIFFRACTION (2.14 Å)