6F9V

Crystal structure of human Angiotensin-1 converting enzyme N-domain in complex with Sampatrilat.

6F9V の概要

• エントリーDOI: 10.2210/pdb6f9v/pdb
• 分子名称: Angiotensin-converting enzyme, DI(HYDROXYETHYL)ETHER, TETRAETHYLENE GLYCOL, ... (14 entities in total)
• 機能のキーワード: angiotensin-1 converting enzyme, ace inhibitor, sampatrilat, hydrolase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 150517.73

構造登録者

Cozier, G.E.,Acharya, K.R. (登録日: 2017-12-15, 公開日: 2018-03-07, 最終更新日: 2024-11-06)

主引用文献

Cozier, G.E.,Schwager, S.L.,Sharma, R.K.,Chibale, K.,Sturrock, E.D.,Acharya, K.R.
Crystal structures of sampatrilat and sampatrilat-Asp in complex with human ACE - a molecular basis for domain selectivity.
FEBS J., 285:1477-1490, 2018

PubMed Abstract: Angiotensin-1-converting enzyme (ACE) is a zinc metallopeptidase that consists of two homologous catalytic domains (known as nACE and cACE) with different substrate specificities. Based on kinetic studies it was previously reported that sampatrilat, a tight-binding inhibitor of ACE, K = 13.8 nm and 171.9 nm for cACE and nACE respectively [Sharma et al., Journal of Chemical Information and Modeling (2016), 56, 2486-2494], was 12.4-fold more selective for cACE. In addition, samAsp, in which an aspartate group replaces the sampatrilat lysine, was found to be a nonspecific and lower micromolar affinity inhibitor. Here, we report a detailed three-dimensional structural analysis of sampatrilat and samAsp binding to ACE using high-resolution crystal structures elucidated by X-ray crystallography, which provides a molecular basis for differences in inhibitor affinity and selectivity for nACE and cACE. The structures show that the specificity of sampatrilat can be explained by increased hydrophobic interactions and a H-bond from Glu403 of cACE with the lysine side chain of sampatrilat that are not observed in nACE. In addition, the structures clearly show a significantly greater number of hydrophilic and hydrophobic interactions with sampatrilat compared to samAsp in both cACE and nACE consistent with the difference in affinities. Our findings provide new experimental insights into ligand binding at the active site pockets that are important for the design of highly specific domain selective inhibitors of ACE.

PubMed: 29476645
DOI: 10.1111/febs.14421

実験手法

X-RAY DIFFRACTION (1.69 Å)