6H5W

Crystal structure of human Angiotensin-1 converting enzyme C-domain in complex with Omapatrilat.

6H5W の概要

• エントリーDOI: 10.2210/pdb6h5w/pdb
• 分子名称: Angiotensin-converting enzyme, 1,2-ETHANEDIOL, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (11 entities in total)
• 機能のキーワード: angiotensin-1 converting enzyme, ace inhibitor, omapatrilat, vasopeptidase inhibitor, hydrolase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 71725.56

構造登録者

Cozier, G.E.,Acharya, K.R. (登録日: 2018-07-25, 公開日: 2018-11-07, 最終更新日: 2024-11-13)

主引用文献

Cozier, G.E.,Arendse, L.B.,Schwager, S.L.,Sturrock, E.D.,Acharya, K.R.
Molecular Basis for Multiple Omapatrilat Binding Sites within the ACE C-Domain: Implications for Drug Design.
J. Med. Chem., 61:10141-10154, 2018

PubMed Abstract: Omapatrilat was designed as a vasopeptidase inhibitor with dual activity against the zinc metallopeptidases angiotensin-1 converting enzyme (ACE) and neprilysin (NEP). ACE has two homologous catalytic domains (nACE and cACE), which exhibit different substrate specificities. Here, we report high-resolution crystal structures of omapatrilat in complex with nACE and cACE and show omapatrilat has subnanomolar affinity for both domains. The structures show nearly identical binding interactions for omapatrilat in each domain, explaining the lack of domain selectivity. The cACE complex structure revealed an omapatrilat dimer occupying the cavity beyond the S subsite, and this dimer had low micromolar inhibition of nACE and cACE. These results highlight residues beyond the S subsite that could be exploited for domain selective inhibition. In addition, it suggests the possibility of either domain specific allosteric inhibitors that bind exclusively to the nonprime cavity or the potential for targeting specific substrates rather than completely inhibiting the enzyme.

PubMed: 30372620
DOI: 10.1021/acs.jmedchem.8b01309

実験手法

X-RAY DIFFRACTION (1.37 Å)