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首页> 外文期刊>Biochemistry >Simulated Interactions between Angiotensin-Converting Enzyme and Substrate Gonadotropin-Releasing Hormone: Novel Insights into Domain Selectivity
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Simulated Interactions between Angiotensin-Converting Enzyme and Substrate Gonadotropin-Releasing Hormone: Novel Insights into Domain Selectivity

机译：血管紧张素转换酶与底物促性腺激素释放激素之间的模拟相互作用：域选择性的新见解。

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Human angiotensin-I converting enzyme (ACE) is a central component of the renin-angiotensin system and a major target for cardiovascular therapies. The somatic form of the enzyme (sACE) comprises two homologous metallopeptidase domains (N and C), each bearing a zinc active site with similar but distinct substrate and inhibitor specificities. On the basis of the recently determined crystal structures of both ACE domains, we have studied their complexes with gonadotropin-releasing hormone (GnRH), which is cleaved releasing both the protected NH_2- and COOH-terminal tripeptides. This is the first molecular modeling study of an ACE-peptide substrate complex that examines the structural basis of ACE's endopeptidase activity and offers novel insights into subsites that are distant from the obligatory binding site and were not identified in the crystal structures. Our data indicate that a bridging interaction between Arg500 of the N-domain and Arg~8 of GnRH that involves a buried chloride ion may account for its role in the specificity of the N-domain for endoproteolytic cleavage of the substrate at the NH_2-terminus in vitro. In support of this, the protected NH_2-terminal dipeptide of GnRH exhibits stronger interactions than the protected COOH-terminal dipeptide with the N-domain of ACE. Further comparison of the models of ACE-substrate complexes promotes our understanding of how the two domains differ in their function and specificity and provides an extension of the pharmacophore model used for structure-based drug design up to the S_7 subsite of the enzyme.
机译：人血管紧张素I转换酶（ACE）是肾素-血管紧张素系统的重要组成部分，也是心血管疗法的主要靶标。酶的体细胞形式（sACE）包含两个同源的金属肽酶结构域（N和C），每个结构域带有一个锌活性位点，具有相似但不同的底物和抑制剂特异性。根据最近确定的两个ACE域的晶体结构，我们研究了它们与促性腺激素释放激素（GnRH）的复合物，该激素被裂解后释放出受保护的NH_2-和COOH-末端三肽。这是对ACE肽底物复合物的首次分子建模研究，该复合物检查了ACE内肽酶活性的结构基础，并对远离强制结合位点且未在晶体结构中鉴定出的亚位点提供了新颖的见解。我们的数据表明，N-结构域的Arg500与GnRH的Arg〜8之间的桥连相互作用涉及掩埋的氯离子，这可能解释了它在N-结构域对内源蛋白在NH_2-末端裂解内质酶裂解的特异性中的作用。体外。支持这一点的是，GnRH的受保护的NH_2末端二肽比受保护的具有ACE的N结构域的COOH末端二肽具有更强的相互作用。 ACE-底物复合物模型的进一步比较增进了我们对这两个域在功能和特异性上如何不同的理解，并为基于结构的药物设计提供了药效团模型扩展到酶的S_7亚位点。

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