Department of Biology and Biochemistry, University of Bath, UK.
FEBS J. 2014 Feb;281(3):943-56. doi: 10.1111/febs.12660. Epub 2013 Dec 24.
Human somatic angiotensin-I converting enzyme (ACE) is a zinc-dependent dipeptidyl carboxypeptidase and a central component of the renin angiotensin aldosterone system (RAAS). Its involvement in the modulation of physiological actions of peptide hormones has positioned ACE as an important therapeutic target for the treatment of hypertension and cardiovascular disorders. Here, we report the crystal structures of the two catalytic domains of human ACE (N- and C-) in complex with FI, the S enantiomer of the phosphinic ACE/ECE-1 (endothelin converting enzyme) dual inhibitor FII, to a resolution of 1.91 and 1.85 Å, respectively. In addition, we have determined the structure of AnCE (an ACE homologue from Drosophila melanogaster) in complex with both isomers. The inhibitor FI (S configuration) can adapt to the active site of ACE catalytic domains and shows key differences in its binding mechanism mostly through the reorientation of the isoxazole phenyl side group at the P₁' position compared with FII (R configuration). Differences in binding are also observed between FI and FII in complex with AnCE. Thus, the new structures of the ACE-inhibitor complexes presented here provide useful information for further exploration of ACE inhibitor pharmacophores involving phosphinic peptides and illustrate the role of chirality in enhancing drug specificity.
人源体血管紧张素转化酶（ACE）是一种锌依赖性二肽羧基肽酶，也是肾素-血管紧张素-醛固酮系统（RAAS）的核心组成部分。它在调节肽类激素的生理作用方面的作用，使 ACE 成为治疗高血压和心血管疾病的重要治疗靶点。在这里，我们报告了人源 ACE（N-和 C-）两个催化结构域与 FI（ACE/ECE-1（内皮素转化酶）双抑制剂 FII 的 S 对映异构体）复合物的晶体结构，分辨率分别为 1.91 和 1.85 Å。此外，我们还确定了来自黑腹果蝇的 ACE 同源物 AnCE 与两种异构体复合物的结构。抑制剂 FI（S 构型）可以适应 ACE 催化结构域的活性部位，与 FII（R 构型）相比，其结合机制主要通过 P₁'位置的异噁唑苯侧基的重定向表现出关键差异。FI 与 FII 分别与 AnCE 形成复合物时，结合也存在差异。因此，这里呈现的 ACE-抑制剂复合物的新结构为进一步探索涉及膦酸肽的 ACE 抑制剂药效团提供了有用信息，并说明了手性在增强药物特异性方面的作用。
