6EN5

Crystal structure A of the Angiotensin-1 converting enzyme N-domain in complex with a diprolyl inhibitor.

6EN5 の概要

• エントリーDOI: 10.2210/pdb6en5/pdb
• 分子名称: Angiotensin-converting enzyme, MAGNESIUM ION, DI(HYDROXYETHYL)ETHER, ... (18 entities in total)
• 機能のキーワード: ace inhibitor angiotensin-i converting enzyme diprolyl inhibitor, hydrolase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 304578.42

構造登録者

Cozier, G.E.,Acharya, K.R.,Fienberg, S.,Chibale, K.,Sturrock, E.D. (登録日: 2017-10-04, 公開日: 2017-12-20, 最終更新日: 2024-11-13)

主引用文献

Fienberg, S.,Cozier, G.E.,Acharya, K.R.,Chibale, K.,Sturrock, E.D.
The Design and Development of a Potent and Selective Novel Diprolyl Derivative That Binds to the N-Domain of Angiotensin-I Converting Enzyme.
J. Med. Chem., 61:344-359, 2018

PubMed Abstract: Angiotensin-I converting enzyme (ACE) is a zinc metalloprotease consisting of two catalytic domains (N- and C-). Most clinical ACE inhibitor(s) (ACEi) have been shown to inhibit both domains nonselectively, resulting in adverse effects such as cough and angioedema. Selectively inhibiting the individual domains is likely to reduce these effects and potentially treat fibrosis in addition to hypertension. ACEi from the GVK Biosciences database were inspected for possible N-domain selective binding patterns. From this set, a diprolyl chemical series was modeled using docking simulations. The series was expanded based on key target interactions involving residues known to impart N-domain selectivity. In total, seven diprolyl compounds were synthesized and tested for N-domain selective ACE inhibition. One compound with an aspartic acid in the P position (compound 16) displayed potent inhibition (K = 11.45 nM) and was 84-fold more selective toward the N-domain. A high-resolution crystal structure of compound 16 in complex with the N-domain revealed the molecular basis for the observed selectivity.

PubMed: 29206036
DOI: 10.1021/acs.jmedchem.7b01478

実験手法

X-RAY DIFFRACTION (1.75 Å)