Department of Biology and Biochemistry, University of Bath, Bath, UK.
Department of Integrative Biomedical Sciences, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa.
FEBS J. 2021 Apr;288(7):2238-2256. doi: 10.1111/febs.15601. Epub 2020 Nov 2.
Angiotensin-1-converting enzyme (ACE) is a key enzyme in the renin-angiotensin-aldosterone and kinin systems where it cleaves angiotensin I and bradykinin peptides, respectively. However, ACE also participates in numerous other physiological functions, can hydrolyse many peptide substrates and has various exo- and endopeptidase activities. ACE achieves this complexity by containing two homologous catalytic domains (N- and C-domains), which exhibit different substrate specificities. Here, we present the first open conformation structures of ACE N-domain and a unique closed C-domain structure (2.0 Å) where the C terminus of a symmetry-related molecule is observed inserted into the active-site cavity and binding to the zinc ion. The open native N-domain structure (1.85 Å) enables comparison with ACE2, a homologue previously observed in open and closed states. An open S _S'-mutant N-domain structure (2.80 Å) includes mutated residues in the S and S' subsites that effect ligand binding, but are distal to the binding site. Analysis of these structures provides important insights into how structural features of the ACE domains are able to accommodate the wide variety of substrates and allow different peptidase activities. DATABASE: The atomic coordinates and structure factors for Open nACE, Open S2_S'-nACE and Native G13-cACE structures have been deposited with codes 6ZPQ, 6ZPT and 6ZPU, respectively, in the RCSB Protein Data Bank, www.pdb.org.
血管紧张素转化酶（ACE）是肾素-血管紧张素-醛固酮和激肽系统中的关键酶，分别切割血管紧张素 I 和缓激肽肽。然而，ACE 还参与许多其他生理功能，可以水解许多肽底物，并具有各种外肽酶和内肽酶活性。ACE 通过包含两个同源催化结构域（N-和 C-结构域）来实现这种复杂性，这两个结构域表现出不同的底物特异性。在这里，我们展示了 ACE N-结构域的第一个开放构象结构和一个独特的封闭 C-结构域结构（2.0Å），其中观察到对称相关分子的 C 末端插入活性位点腔并与锌离子结合。开放的天然 N-结构域结构（1.85Å）使我们能够与 ACE2 进行比较，ACE2 是以前在开放和封闭状态下观察到的同源物。开放的 S _S'-突变 N-结构域结构（2.80Å）包含在 S 和 S'亚位点中突变的残基，这些残基影响配体结合，但远离结合位点。这些结构的分析提供了重要的见解，了解 ACE 结构域的结构特征如何能够容纳各种底物并允许不同的肽酶活性。数据库：Open nACE、Open S2_S'-nACE 和 Native G13-cACE 结构的原子坐标和结构因子已分别以代码 6ZPQ、6ZPT 和 6ZPU 存入 RCSB 蛋白质数据库，www.pdb.org。
