Simulated Interactions between Angiotensin-Converting Enzyme and Substrate Gonadotropin-Releasing Hormone: Novel Insights into Domain Selectivity

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• 作者：Athanasios Papakyriakou ; Georgios A. Spyroulias ; Edward D. Sturrock ; Evy Manessi-Zoupa ; Paul Cordopatis
• 刊名：Biochemistry
• 出版年：2007
• 出版时间：July 31, 2007
• 年：2007
• 卷：46
• 期：30
• 页码：8753 - 8765
• 全文大小：1400K
• 年卷期：v.46,no.30(July 31, 2007)
• ISSN：1520-4995

文摘

Human angiotensin-I converting enzyme (ACE) is a central component of the renin-angiotensinsystem and a major target for cardiovascular therapies. The somatic form of the enzyme (sACE) comprisestwo homologous metallopeptidase domains (N and C), each bearing a zinc active site with similar butdistinct substrate and inhibitor specificities. On the basis of the recently determined crystal structures ofboth ACE domains, we have studied their complexes with gonadotropin-releasing hormone (GnRH), whichis cleaved releasing both the protected NH₂- and COOH-terminal tripeptides. This is the first molecularmodeling study of an ACE-peptide substrate complex that examines the structural basis of ACE'sendopeptidase activity and offers novel insights into subsites that are distant from the obligatory bindingsite and were not identified in the crystal structures. Our data indicate that a bridging interaction betweenArg500 of the N-domain and Arg⁸ of GnRH that involves a buried chloride ion may account for its rolein the specificity of the N-domain for endoproteolytic cleavage of the substrate at the NH₂-terminus invitro. In support of this, the protected NH₂-terminal dipeptide of GnRH exhibits stronger interactionsthan the protected COOH-terminal dipeptide with the N-domain of ACE. Further comparison of the modelsof ACE-substrate complexes promotes our understanding of how the two domains differ in their functionand specificity and provides an extension of the pharmacophore model used for structure-based drugdesign up to the S₇ subsite of the enzyme.