7Z70

Crystal structure of Angiotensin-1 converting enzyme C-domain in complex with fosinoprilat

7Z70 の概要

• エントリーDOI: 10.2210/pdb7z70/pdb
• 分子名称: Angiotensin-converting enzyme, CHLORIDE ION, alpha-D-mannopyranose-(1-3)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta-D-glucopyranose, ... (11 entities in total)
• 機能のキーワード: angiotensin-1 converting enzyme, fosinoprilat, fosinopril, metalloprotease, 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: 71003.71

構造登録者

Cozier, G.E.,Acharya, K.R. (登録日: 2022-03-14, 公開日: 2022-06-22, 最終更新日: 2024-11-13)

主引用文献

Cozier, G.E.,Newby, E.C.,Schwager, S.L.U.,Isaac, R.E.,Sturrock, E.D.,Acharya, K.R.
Structural basis for the inhibition of human angiotensin-1 converting enzyme by fosinoprilat.
Febs J., 289:6659-6671, 2022

PubMed Abstract: Human angiotensin I-converting enzyme (ACE) has two isoforms, somatic ACE (sACE) and testis ACE (tACE). The functions of sACE are widespread, with its involvement in blood pressure regulation most extensively studied. sACE is composed of an N-domain (nACE) and a C-domain (cACE), both catalytically active but have significant structural differences, resulting in different substrate specificities. Even though ACE inhibitors are used clinically, they need much improvement because of serious side effects seen in patients (~ 25-30%) with long-term treatment due to nonselective inhibition of nACE and cACE. Investigation into the distinguishing structural features of each domain is therefore of vital importance for the development of domain-specific inhibitors with minimal side effects. Here, we report kinetic data and high-resolution crystal structures of both nACE (1.75 Å) and cACE (1.85 Å) in complex with fosinoprilat, a clinically used inhibitor. These structures allowed detailed analysis of the molecular features conferring domain selectivity by fosinoprilat. Particularly, altered hydrophobic interactions were observed to be a contributing factor. These experimental data contribute to improved understanding of the structural features that dictate ACE inhibitor domain selectivity, allowing further progress towards designing novel 2nd-generation domain-specific potent ACE inhibitors suitable for clinical administration, with a variety of potential future therapeutic benefits. DATABASE: The atomic coordinates and structure factors for nACE-fosinoprilat and cACE-fosinoprilat structures have been deposited with codes 7Z6Z and 7Z70, respectively, in the RCSB Protein Data Bank, www.pdb.org.

PubMed: 35653492
DOI: 10.1111/febs.16543

実験手法

X-RAY DIFFRACTION (1.85 Å)