9SSA

Human angiotensin 1-converting enzyme C-domain in complex with zofenoprilat

9SSA の概要

• エントリーDOI: 10.2210/pdb9ssa/pdb
• 分子名称: Angiotensin-converting enzyme, CHLORIDE ION, IMIDAZOLE, ... (12 entities in total)
• 機能のキーワード: inhibitor, complex, 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: 71360.40

構造登録者

Gregory, K.S.,Acharya, K.R. (登録日: 2025-09-25, 公開日: 2026-02-18)

主引用文献

Gregory, K.S.,Ramasamy, V.,Sturrock, E.D.,Acharya, K.R.
Kinetic and structural characterisation of domain-specific angiotensin I-converting enzyme inhibition by captopril, rentiapril and zofenoprilat.
Febs J., 2026

PubMed Abstract: Angiotensin I-converting enzyme (ACE) is a zinc-dependent dipeptidyl carboxypeptidase involved in blood pressure regulation through proteolysis of angiotensin I (Ang-I) into the potent vasoconstrictor, angiotensin II (Ang-II). Inhibition of ACE is therefore used for the treatment of hypertension, heart failure, myocardial infarction, stroke and chronic kidney disease. Current ACE inhibitors (ACEi) bind both the N- and C-catalytic domains of ACE (referred to as nACE and cACE), and this has been linked to the occurrence of side effects due to the wide substrate specificity of ACE. The development of domain selective ACEi with reduced side effects is therefore key for improved therapeutic intervention. Understanding how current ACEi bind nACE and cACE, and their differences in domain selectivity should aid structure-based development of more selective ACEi by identifying different chemical groups that increase or decrease selectivity. We present the kinetic and structural characterisation of nACE and cACE with three thiolate ACEi, captopril (K, nACE = 2.53 nm and cACE = 2.04 nm), rentiapril (monomer K, nACE = 2.22 nm and cACE = 6.77 nm) and zofenoprilat (K, nACE = 2.86 nm and cACE = 0.61 nm). Detailed structural analysis indicated that the S2' subsite likely contributes to the variation in domain selectivity observed for rentiapril and zofenoprilat due to differences in hydrophobicity and displacement of water molecules that contribute to ACE's hydration shell. Interestingly, in the cACE crystal structure, rentiapril bound as a dimer, and kinetic data revealed that both the monomeric and dimeric (dimer K, nACE = 15.11 nm and cACE = 36.38 nm) forms of rentiapril inhibit ACE with nanomolar affinity.

PubMed: 41631382
DOI: 10.1111/febs.70428

実験手法

X-RAY DIFFRACTION (1.9 Å)