Molecular Basis for Multiple Omapatrilat Binding Sites within the ACE C-Domain: Implications for Drug Design
Molecular Basis for Multiple Omapatrilat Binding Sites within the ACE C-Domain: Implications for Drug Design
复制标题
DOI：
10.1021/acs.jmedchem.8b01309
复制
发表时间：
2018-11-22
影响因子：
7.3
通讯作者：
Acharya, K. Ravi
中科院分区：
文献类型：
--
作者：
Cozier, Gyles E.;Arendse, Lauren B.;Acharya, K. Ravi
奥马曲拉是一种血管肽酶抑制剂，对锌金属肽酶血管紧张素-1转换酶（ACE）和脑啡肽酶（NEP）具有双重活性。ACE具有两个同源的催化结构域（nACE和cACE），其表现出不同的底物特异性。在这里，我们报告高分辨率的晶体结构omapatrilat与nACE和cACE的复合物，并显示omapatrilat具有亚纳摩尔的亲和力，这两个领域。结构显示几乎相同的omapatrilat在每个域的结合相互作用，解释缺乏域的选择性。cACE复合物结构显示omapatrilat二聚体占据S-2亚位点以外的空腔，并且该二聚体对nACE和cACE具有低微摩尔抑制。这些结果突出了可用于结构域选择性抑制的S-2亚位点以外的残基。此外，它表明，无论是域特异性变构抑制剂，专门结合到nonprime腔或针对特定的底物，而不是完全抑制酶的潜力的可能性。
Omapatrilat was designed as a vasopeptidase inhibitor with dual activity against the zinc metallopeptidases angiotensin-1 converting enzyme (ACE) and neprilysin (NEP). ACE has two homologous catalytic domains (nACE and cACE), which exhibit different substrate specificities. Here, we report high-resolution crystal structures of omapatrilat in complex with nACE and cACE and show omapatrilat has subnanomolar affinity for both domains. The structures show nearly identical binding interactions for omapatrilat in each domain, explaining the lack of domain selectivity. The cACE complex structure revealed an omapatrilat dimer occupying the cavity beyond the S-2 subsite, and this dimer had low micromolar inhibition of nACE and cACE. These results highlight residues beyond the S-2 subsite that could be exploited for domain selective inhibition. In addition, it suggests the possibility of either domain specific allosteric inhibitors that bind exclusively to the nonprime cavity or the potential for targeting specific substrates rather than completely inhibiting the enzyme.