Crystal structures of sampatrilat and sampatrilat-Asp in complex with human ACE - a molecular basis for domain selectivity.
Crystal structures of sampatrilat and sampatrilat-Asp in complex with human ACE - a molecular basis for domain selectivity.
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DOI：
10.1111/febs.14421
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发表时间：
2018-04
期刊：
影响因子：
--
通讯作者：
Acharya KR
中科院分区：
文献类型：
--
作者：
Cozier GE;Schwager SL;Sharma RK;Chibale K;Sturrock ED;Acharya KR
血管紧张素1转换酶（ACE）是一种锌金属肽酶，由两个具有不同底物特异性的同源催化结构域（称为nACE和cACE）组成。基于动力学研究，先前报道了sampartilat（ACE的紧密结合抑制剂）对于cACE和nACE的Ki分别为13.8 nm和171.9 nm [Sharma等人，Journal of Chemical Information and Modeling（2016），56，2486-2494]，对cACE的选择性高12.4倍。此外，samAsp，其中天冬氨酸基团取代sampartirat赖氨酸，被发现是一种非特异性和较低的微摩尔亲和力抑制剂。在这里，我们使用X射线晶体学阐明的高分辨率晶体结构报告了sampartilat和samAsp与ACE结合的详细三维结构分析，这为nACE和cACE的抑制剂亲和力和选择性差异提供了分子基础。结构表明，sampatrilat的特异性可以通过增加的疏水相互作用和来自cACE的Glu 403与sampatrilat的赖氨酸侧链的H-键来解释，这在nACE中未观察到。此外，在cACE和nACE中，与samAsp相比，结构清楚地显示与sampartirat的亲水和疏水相互作用的数量显著更大，这与亲和力的差异一致。我们的研究结果提供了新的实验见解配体结合的活性位点口袋，是非常重要的高度特异性的结构域选择性抑制剂的ACE的设计。与sampatrilat和sampatrilat-Asp复合物（分别为6 F9 V、6 F9 R、6 F9 T和6 F9 U）结合的ACE的N-和C-结构域的原子坐标和结构因子已保存在Protein Data Bank，Research Collaboratory for Structural Bioinformatics，Rutgers University，新玩法，NJ（http：//www.rcsb.org/）中。
Angiotensin‐1‐converting enzyme (ACE) is a zinc metallopeptidase that consists of two homologous catalytic domains (known as nACE and cACE) with different substrate specificities. Based on kinetic studies it was previously reported that sampatrilat, a tight‐binding inhibitor of ACE, K i = 13.8 nm and 171.9 nm for cACE and nACE respectively [Sharma et al., Journal of Chemical Information and Modeling (2016), 56, 2486–2494], was 12.4‐fold more selective for cACE. In addition, samAsp, in which an aspartate group replaces the sampatrilat lysine, was found to be a nonspecific and lower micromolar affinity inhibitor. Here, we report a detailed three‐dimensional structural analysis of sampatrilat and samAsp binding to ACE using high‐resolution crystal structures elucidated by X‐ray crystallography, which provides a molecular basis for differences in inhibitor affinity and selectivity for nACE and cACE. The structures show that the specificity of sampatrilat can be explained by increased hydrophobic interactions and a H‐bond from Glu403 of cACE with the lysine side chain of sampatrilat that are not observed in nACE. In addition, the structures clearly show a significantly greater number of hydrophilic and hydrophobic interactions with sampatrilat compared to samAsp in both cACE and nACE consistent with the difference in affinities. Our findings provide new experimental insights into ligand binding at the active site pockets that are important for the design of highly specific domain selective inhibitors of ACE. The atomic coordinates and structure factors for N‐ and C‐domains of ACE bound to sampatrilat and sampatrilat‐Asp complexes (6F9V, 6F9R, 6F9T and 6F9U respectively) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).
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影响因子：
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