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Angiotensin‐converting enzyme open for business: structural insights into the subdomain dynamics
The FEBS Journal ( IF 5.4 ) Pub Date : 2020-10-17 , DOI: 10.1111/febs.15601
Gyles E Cozier 1 , Lizelle Lubbe 2 , Edward D Sturrock 2 , K Ravi Acharya 1
Affiliation  

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 S2_S′‐mutant N‐domain structure (2.80 Å) includes mutated residues in the S2 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.

中文翻译:

血管紧张素转换酶向企业开放:对子域动力学的结构见解

血管紧张素-1转换酶(ACE)是肾素-血管紧张素-醛固酮和激肽系统中的关键酶,它们分别裂解血管紧张素I和缓激肽。但是,ACE还参与许多其他生理功能,可以水解许多肽底物,并具有各种外切和内切肽酶活性。ACE通过包含两个同源的催化结构域(N和C结构域)实现了这种复杂性,这两个催化结构域表现出不同的底物特异性。在这里,我们介绍了ACE N域的第一个开放构象结构和一个独特的封闭C结构域(2.0Å),其中观察到对称相关分子的C末端插入了活性位腔并与锌结合离子。开放的本机N域结构(1.85Å)可与ACE2进行比较,以前在打开和关闭状态下观察到的同系物。一个开放的S2 _S'-突变N结构域结构(2.80Å)包括影响配体结合的S 2和S'亚位点的突变残基,但位于结合位点的远端。这些结构的分析为ACE域的结构特征如何适应各种底物并允许不同的肽酶活性提供了重要的见识。
更新日期:2020-10-17
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