Structural basis for the inhibition of human angiotensin-1 converting enzyme by fosinoprilat.
Structural basis for the inhibition of human angiotensin-1 converting enzyme by fosinoprilat.
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DOI：
10.1111/febs.16543
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发表时间：
2022-11
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影响因子：
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人血管紧张素I转换酶（ACE）有两种异构体：躯体ACE （sACE）和睾丸ACE （tACE）。sACE的功能广泛，其参与血压调节的研究最为广泛。sACE由N -结构域（nACE）和C -结构域（cACE）组成，两者都具有催化活性，但具有显著的结构差异，导致不同的底物特异性。尽管临床上使用了ACE抑制剂，但由于nACE和cACE的非选择性抑制，长期治疗的患者（~ 25-30%）出现了严重的副作用，因此它们需要大量改进。因此，研究每个结构域的独特结构特征对于开发具有最小副作用的结构域特异性抑制剂至关重要。在这里，我们报告了nACE （1.75 Å）和cACE （1.85 Å）与fosinoprilat（一种临床使用的抑制剂）复合物的动力学数据和高分辨率晶体结构。这些结构允许通过fosinoprilat详细分析分子特征，赋予结构域选择性。特别是，改变的疏水相互作用被观察到是一个促成因素。这些实验数据有助于提高对ACE抑制剂结构域选择性的结构特征的理解，从而进一步设计出适合临床给药的新型第二代结构域特异性强效ACE抑制剂，并具有各种潜在的未来治疗益处。nACE - fosinoprilat和cACE - fosinoprilat结构的原子坐标和结构因子分别以代码7Z6Z和7Z70存储在RCSB蛋白质数据库www.pdb.org中。对血管紧张素I -转换酶（ACE） N -和C -结构域的高分辨率晶体结构与fosinoprilat复合物的分析提供了进一步了解高亲和力结构域特异性抑制的需求，这是减少针对ACE治疗的副作用所必需的。此外，这些数据强调了需要对fosinoprilat进行修改或重新设计，以开发通过ACE类似物起作用的新型杀虫剂。
Human angiotensin I‐converting enzyme (ACE) has two isoforms, somatic ACE (sACE) and testis ACE (tACE). The functions of sACE are widespread, with its involvement in blood pressure regulation most extensively studied. sACE is composed of an N‐domain (nACE) and a C‐domain (cACE), both catalytically active but have significant structural differences, resulting in different substrate specificities. Even though ACE inhibitors are used clinically, they need much improvement because of serious side effects seen in patients (~ 25–30%) with long‐term treatment due to nonselective inhibition of nACE and cACE. Investigation into the distinguishing structural features of each domain is therefore of vital importance for the development of domain‐specific inhibitors with minimal side effects. Here, we report kinetic data and high‐resolution crystal structures of both nACE (1.75 Å) and cACE (1.85 Å) in complex with fosinoprilat, a clinically used inhibitor. These structures allowed detailed analysis of the molecular features conferring domain selectivity by fosinoprilat. Particularly, altered hydrophobic interactions were observed to be a contributing factor. These experimental data contribute to improved understanding of the structural features that dictate ACE inhibitor domain selectivity, allowing further progress towards designing novel 2nd‐generation domain‐specific potent ACE inhibitors suitable for clinical administration, with a variety of potential future therapeutic benefits. The atomic coordinates and structure factors for nACE‐fosinoprilat and cACE‐fosinoprilat structures have been deposited with codes 7Z6Z and 7Z70, respectively, in the RCSB Protein Data Bank, www.pdb.org. Analysis of high‐resolution crystal structures of angiotensin I‐converting enzyme (ACE) N‐ and C‐domains in complex with fosinoprilat provide further insights into the requirements for high‐affinity domain‐specific inhibition that is required to reduce side effects of treatments that target ACE. In addition, the data highlights where modifications or redesign of fosinoprilat are needed to develop novel insecticides that act via ACE analogues.
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DOI：
10.1042/cs20130403
发表时间：
2014-02
期刊：
Clinical science (London, England : 1979)
影响因子：
--
作者：
Douglas RG;Sharma RK;Masuyer G;Lubbe L;Zamora I;Acharya KR;Chibale K;Sturrock ED
通讯作者：
Sturrock ED
DOI：
10.1038/nrd1227
发表时间：
2003-11
期刊：
Nature reviews. Drug discovery
影响因子：
--
作者：
Acharya KR;Sturrock ED;Riordan JF;Ehlers MR
通讯作者：
Ehlers MR
DOI：
10.1111/febs.15601
发表时间：
2021-04
期刊：
The FEBS journal
影响因子：
--
作者：
Cozier GE;Lubbe L;Sturrock ED;Acharya KR
通讯作者：
Acharya KR
影响因子：
4.1
作者：
Cashman, John S.;Cozier, Gyles E.;Acharya, K. Ravi
通讯作者：
Acharya, K. Ravi
影响因子：
7.3
作者：
Cozier, Gyles E.;Arendse, Lauren B.;Acharya, K. Ravi
通讯作者：
Acharya, K. Ravi