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首页> 外文期刊>Biochemistry >The Structure of Testis Angiotensin-Converting Enzyme in Complex with the C Domain-Specific Inhibitor RXPA380
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The Structure of Testis Angiotensin-Converting Enzyme in Complex with the C Domain-Specific Inhibitor RXPA380

机译：用C域特异性抑制剂RxPA380复合睾丸血管紧张素转换酶的结构

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摘要

Angiotensin I-converting enzyme (ACE) is central to the regulation of the renin-angiotensin system and is a key therapeutic target for combating hypertension and related cardiovascular diseases. Currently available drugs bind both active sites of its two homologous domains, although it is now understood that these domains function differently in vivo. The recently solved crystal structures of both domains (N and C) open the door to new domain-specific inhibitor design, taking advantage of the differences between these two large active sites. Here we present the first crystal structure at a resolution of 2.25 A of testis ACE (identical to the C domain of somatic ACE) with the highly C-domain-specific phosphinic inhibitor, RXPA380. Testis ACE retains the same conformation as seen in previously determined inhibitor complexes, but the RXPA380 central backbone conformation is more similar to that seen for the inhibitor captopril than enalaprilat. The RXPA380 molecule occupies more subsites of the testis ACE active site than the previously determined inhibitors and possesses bulky moieties that extend into the S_2' and S_2 subsites. Thus the high affinity of RXPA380 for the testis ACE/somatic ACE C domain is explained by the interaction of these bulky moieties with residues unique to these domains, specifically Phe 391, Val 379, and Val 380, that are not found in the N domain. The characterization of the extended active site and the binding of a potent C-domain-selective inhibitor provide the first structural data for the design of truly domain-specific pharmacophores.
机译：血管紧张素I-转换酶（ACE）是肾素 - 血管紧张素系统调节的核心，是调控高血压和相关心血管疾病的关键治疗靶标。目前可用的药物结合其两个同源域的活性位点，尽管现在被理解，这些域在体内以不同方式函数。最近解决了两个域（n和c）的晶体结构，对新的域特异性抑制剂设计开门，利用这两个大型活跃点之间的差异。在这里，我们以高度C域特异性膦抑制剂RxPA380呈现了高度C-结构域的磷酸葡萄糖抑制剂的第一种晶体结构。睾丸ACE保持与先前确定的抑制剂复合物中所见相同的构象，但RXPA380中央骨干构象更类似于对抑制剂卡托普利观察到的比烯丙酮。 RXPA380分子占据睾丸ACE活性位点的更多子区域，而不是先前确定的抑制剂，并具有延伸到S_2'和S_2底座的笨重部分。因此，对睾丸ACE /体细胞ACE C结构域的RXPA380的高亲和力通过这些庞大的部分与这些结构域独特的残基的相互作用，特别是PHE 391，VAL 379和VAL 380，其在N结构域中未发现。延伸的活性位点的表征和有效的C-结构域选择性抑制剂的结合提供了真正域特异性药物设计的第一结构数据。

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  • 来源
    《Biochemistry》 |2007年第18期|共6页
  • 作者

    Hazel R. Corradi; Itai Chitapi; B. Trevor Sewell;

  • 作者单位

    Department of Biology and Biochemistry University of Bath Claverton Down Bath BA2 7AY United Kingdom Division of Medical Biochemistry and Institute of Infectious Disease and Molecular Medicine University of Cape Town Observatory 7925 South Afri;

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  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 生物化学;
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