Department of Biology and Biochemistry, University of Bath, UK.
FEBS J. 2012 Dec;279(24):4525-34. doi: 10.1111/febs.12038. Epub 2012 Nov 22.
Human somatic angiotensin-1 converting enzyme (ACE) is a zinc-dependent exopeptidase, that catalyses the conversion of the decapeptide angiotensin I to the octapeptide angiotensin II, by removing a C-terminal dipeptide. It is the principal component of the renin-angiotensin-aldosterone system that regulates blood pressure. Hence it is an important therapeutic target for the treatment of hypertension and cardiovascular disorders. Here, we report the structures of an ACE homologue from Drosophila melanogaster (AnCE; a proven structural model for the more complex human ACE) co-crystallized with mammalian peptide substrates (bradykinin, Thr(6) -bradykinin, angiotensin I and a snake venom peptide inhibitor, bradykinin-potentiating peptide-b). The structures determined at 2-Å resolution illustrate that both angiotensin II (the cleaved product of angiotensin I by AnCE) and bradykinin-potentiating peptide-b bind in an analogous fashion at the active site of AnCE, but also exhibit significant differences. In addition, the binding of Arg-Pro-Pro, the cleavage product of bradykinin and Thr(6) - bradykinin, provides additional detail of the general peptide binding in AnCE. Thus the new structures of AnCE complexes presented here improves our understanding of the binding of peptides and the mechanism by which peptides inhibit this family of enzymes.
The atomic coordinates and structure factors for AnCE-Ang II (code 4AA1), AnCE-BPPb (code 4AA2), AnCE-BK (code 4ASQ) and AnCE-Thr6-BK (code 4ASR) complexes have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/)
• AnCE cleaves Ang I by enzymatic study (View interaction) • Bradykinin and AnCE bind by x-ray crystallography (View interaction) • BPP and AnCE bind by x-ray crystallography (View interaction) • AnCE cleaves Bradykinin by enzymatic study (View interaction) • Ang II and AnCE bind by x-ray crystallography (View interaction).
人类躯体血管紧张素转换酶（ACE）是一种锌依赖性外肽酶，通过去除 C 末端二肽，催化十肽血管紧张素 I 转化为八肽血管紧张素 II。它是肾素-血管紧张素-醛固酮系统的主要成分，调节血压。因此，它是治疗高血压和心血管疾病的重要治疗靶点。在这里，我们报告了来自果蝇（AnCE；一种经过验证的人类 ACE 更复杂结构的结构模型）的 ACE 同源物与哺乳动物肽底物（缓激肽、Thr（6）-缓激肽、血管紧张素 I 和蛇毒肽抑制剂缓激肽增强肽-b）共结晶的结构。在 2 Å 分辨率下确定的结构表明，血管紧张素 II（AnCE 切割血管紧张素 I 的产物）和缓激肽增强肽-b 以类似的方式结合在 AnCE 的活性部位，但也存在显著差异。此外，缓激肽和 Thr（6）-缓激肽的切割产物 Arg-Pro-Pro 的结合提供了 AnCE 中一般肽结合的更多细节。因此，这里呈现的新的 AnCE 复合物结构提高了我们对肽结合的理解，以及肽抑制该酶家族的机制。
AnCE-Ang II（代码 4AA1）、AnCE-BPPb（代码 4AA2）、AnCE-BK（代码 4ASQ）和 AnCE-Thr6-BK（代码 4ASR）复合物的原子坐标和结构因子已被存入蛋白质数据库，研究合作结构生物信息学，罗格斯大学，新泽西州新不伦瑞克（http://www.rcsb.org/）
• AnCE 通过酶促研究切割 Ang I（查看相互作用）• 缓激肽和 AnCE 通过 X 射线晶体学结合（查看相互作用）• BPP 和 AnCE 通过 X 射线晶体学结合（查看相互作用）• AnCE 通过酶促研究切割缓激肽（查看相互作用）• Ang II 和 AnCE 通过 X 射线晶体学结合（查看相互作用）。
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