Zhang Haitao, Han Gye Won, Batyuk Alexander, Ishchenko Andrii, White Kate L, Patel Nilkanth, Sadybekov Anastasiia, Zamlynny Beata, Rudd Michael T, Hollenstein Kaspar, Tolstikova Alexandra, White Thomas A, Hunter Mark S, Weierstall Uwe, Liu Wei, Babaoglu Kerim, Moore Eric L, Katz Ryan D, Shipman Jennifer M, Garcia-Calvo Margarita, Sharma Sujata, Sheth Payal, Soisson Stephen M, Stevens Raymond C, Katritch Vsevolod, Cherezov Vadim
Department of Chemistry, Bridge Institute, University of Southern California, Los Angeles, California 90089, USA.
Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou, Zhejiang 310058, China.
Nature. 2017 Apr 20;544(7650):327-332. doi: 10.1038/nature22035. Epub 2017 Apr 5.
The angiotensin II receptors ATR and ATR serve as key components of the renin-angiotensin-aldosterone system. ATR has a central role in the regulation of blood pressure, but the function of ATR is unclear and it has a variety of reported effects. To identify the mechanisms that underlie the differences in function and ligand selectivity between these receptors, here we report crystal structures of human ATR bound to an ATR-selective ligand and to an ATR/ATR dual ligand, capturing the receptor in an active-like conformation. Unexpectedly, helix VIII was found in a non-canonical position, stabilizing the active-like state, but at the same time preventing the recruitment of G proteins or β-arrestins, in agreement with the lack of signalling responses in standard cellular assays. Structure-activity relationship, docking and mutagenesis studies revealed the crucial interactions for ligand binding and selectivity. Our results thus provide insights into the structural basis of the distinct functions of the angiotensin receptors, and may guide the design of new selective ligands.
血管紧张素 II 受体 ATR 和 ATR 是肾素 - 血管紧张素 - 醛固酮系统的关键组成部分。ATR 在血压调节中起核心作用，但 ATR 的功能尚不清楚，且有多种不同的报道效应。为了确定这些受体在功能和配体选择性上存在差异的潜在机制，我们在此报告了与 ATR 选择性配体和 ATR/ATR 双配体结合的人 ATR 的晶体结构，捕获到处于类似活性构象的受体。出乎意料的是，发现螺旋 VIII 处于非典型位置，稳定了类似活性的状态，但同时阻止了 G 蛋白或 β - 抑制蛋白的募集，这与标准细胞试验中缺乏信号反应一致。构效关系、对接和诱变研究揭示了配体结合和选择性的关键相互作用。因此，我们的结果为血管紧张素受体不同功能的结构基础提供了见解，并可能指导新型选择性配体的设计。
