Angiotensin-converting enzyme open for business: structural insights into the subdomain dynamics.
Angiotensin-converting enzyme open for business: structural insights into the subdomain dynamics.
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DOI：
10.1111/febs.15601
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发表时间：
2021-04
期刊：
影响因子：
--
通讯作者：
Acharya KR
中科院分区：
文献类型：
--
作者：
Cozier GE;Lubbe L;Sturrock ED;Acharya KR
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，它分别裂解血管紧张素- 1和缓激肽。然而，ACE还参与许多其他生理功能，可以水解许多肽底物，并具有多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，我们提出了ACE N域的第一个开放构象结构和一个独特的封闭C域结构（2.0 Å），其中对称相关分子的C端插入活性位点腔并与锌离子结合。开放的原生N域结构（1.85 Å）可以与ACE2进行比较，ACE2是先前在开放和封闭状态下观察到的同源物。开放的S2_S ‘突变N -结构域结构（2.80 Å）包括影响配体结合的S2和S ’亚位的突变残基，但它们位于结合位点的远端。对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适应各种底物并允许不同的肽酶活性。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存储在RCSB蛋白数据库中，www.pdb.org Angiotensin‐1‐conversion enzyme （ACE）具有广泛的底物特异性和生理功能。第一个开放结构的ACE N - domain （nACE）显示出与ACE2 （ACE同源物）相似的开放结构域，允许底物结合，并提示扩展了内多肽酶活性的结合位点。第二个突变体nACE开放结构检查远端残基在配体结合中的作用。此外，一种新的ACE C‐结构域结构解释了长肽底物结合。
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. 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 Angiotensin‐1‐converting enzyme (ACE) has broad substrate specificity and physiological functions. The first open structure of ACE N‐domain (nACE) presented here shows similar domain opening as ACE2 (close ACE homologue) that allows substrates to bind, and suggests extended binding site for endopeptidase activity. A second mutant nACE open structure examines the role of distal residues on ligand binding. In addition, a novel ACE C‐domain structure explains long peptide substrate binding.
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DOI：
10.1111/febs.13647
发表时间：
2016-03
期刊：
The FEBS journal
影响因子：
--
作者：
Larmuth KM;Masuyer G;Douglas RG;Schwager SL;Acharya KR;Sturrock ED
通讯作者：
Sturrock ED
影响因子：
4.6
作者：
Masuyer G;Schwager SL;Sturrock ED;Isaac RE;Acharya KR
通讯作者：
Acharya KR
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
DOI：
10.1002/prot.340230412
发表时间：
1995-12-01
期刊：
PROTEINS-STRUCTURE FUNCTION AND GENETICS
影响因子：
--
作者：
Frishman, D;Argos, P
通讯作者：
Argos, P
影响因子：
7.3
作者：
Cozier, Gyles E.;Arendse, Lauren B.;Acharya, K. Ravi
通讯作者：
Acharya, K. Ravi