Crystal structure of the human angiotensin-converting enzyme-lisinopril complex
Crystal structure of the human angiotensin-converting enzyme-lisinopril complex
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DOI：
10.1038/nature01370
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发表时间：
2003-01-30
期刊：
影响因子：
64.8
通讯作者：
Acharya, KR
中科院分区：
文献类型：
--
作者：
Natesh, R;Schwager, SLU;Acharya, KR
血管紧张素转换酶（ACE）通过将血管紧张素I的羧基末端His-Leu二肽切割成有效的血管加压八肽血管紧张素II，在心血管功能中具有关键作用。ACE抑制剂是治疗高血压、心力衰竭、心肌梗死和糖尿病肾病的一线药物。值得注意的是，这些抑制剂是在不了解人ACE结构的情况下开发的，而是基于与羧肽酶A的假定机制同源性而设计的（1）。在这里，我们提出了人类睾丸ACE及其与最广泛使用的抑制剂之一赖诺普利（N-2-[（S）-1-羧基-3-苯丙基]-L-赖氨酰-L-脯氨酸;也称为Prinivil或Zestril）的复合物的X射线结构，分辨率为2.0埃。ACE的三维结构分析表明，它与羧肽酶A几乎没有相似性，而是类似于神经溶解素（2）和激烈热球菌羧肽酶（3）-锌金属肽酶，与ACE没有可检测的序列相似性。该结构提供了一个机会，设计域选择性ACE抑制剂，可能会表现出新的药理学概况。
Angiotensin-converting enzyme (ACE) has a critical role in cardiovascular function by cleaving the carboxy terminal His-Leu dipeptide from angiotensin I to produce a potent vasopressor octapeptide, angiotensin II. Inhibitors of ACE are a first line of therapy for hypertension, heart failure, myocardial infarction and diabetic nephropathy. Notably, these inhibitors were developed without knowledge of the structure of human ACE, but were instead designed on the basis of an assumed mechanistic homology with carboxypeptidase A(1). Here we present the X-ray structure of human testicular ACE and its complex with one of the most widely used inhibitors, lisinopril (N-2-[(S)-1-carboxy-3-phenylpropyl]-L-lysyl-L-proline; also known as Prinivil or Zestril), at 2.0 Angstrom resolution. Analysis of the three-dimensional structure of ACE shows that it bears little similarity to that of carboxypeptidase A, but instead resembles neurolysin(2) and Pyrococcus furiosus carboxypeptidase(3)-zinc metallopeptidases with no detectable sequence similarity to ACE. The structure provides an opportunity to design domain-selective ACE inhibitors that may exhibit new pharmacological profiles.