Zhang Haitao, Unal Hamiyet, Gati Cornelius, Han Gye Won, Liu Wei, Zatsepin Nadia A, James Daniel, Wang Dingjie, Nelson Garrett, Weierstall Uwe, Sawaya Michael R, Xu Qingping, Messerschmidt Marc, Williams Garth J, Boutet Sébastien, Yefanov Oleksandr M, White Thomas A, Wang Chong, Ishchenko Andrii, Tirupula Kalyan C, Desnoyer Russell, Coe Jesse, Conrad Chelsie E, Fromme Petra, Stevens Raymond C, Katritch Vsevolod, Karnik Sadashiva S, Cherezov Vadim
Department of Biological Sciences, Bridge Institute, University of Southern California, Los Angeles, CA 90089, USA.
Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
Cell. 2015 May 7;161(4):833-44. doi: 10.1016/j.cell.2015.04.011. Epub 2015 Apr 23.
Angiotensin II type 1 receptor (AT(1)R) is a G protein-coupled receptor that serves as a primary regulator for blood pressure maintenance. Although several anti-hypertensive drugs have been developed as AT(1)R blockers (ARBs), the structural basis for AT(1)R ligand-binding and regulation has remained elusive, mostly due to the difficulties of growing high-quality crystals for structure determination using synchrotron radiation. By applying the recently developed method of serial femtosecond crystallography at an X-ray free-electron laser, we successfully determined the room-temperature crystal structure of the human AT(1)R in complex with its selective antagonist ZD7155 at 2.9-Å resolution. The AT(1)R-ZD7155 complex structure revealed key structural features of AT(1)R and critical interactions for ZD7155 binding. Docking simulations of the clinically used ARBs into the AT(1)R structure further elucidated both the common and distinct binding modes for these anti-hypertensive drugs. Our results thereby provide fundamental insights into AT(1)R structure-function relationship and structure-based drug design.
血管紧张素II 1型受体（AT(1)R）是一种G蛋白偶联受体，是维持血压的主要调节因子。尽管已经开发了几种作为AT(1)R阻滞剂（ARB）的抗高血压药物，但AT(1)R配体结合和调节的结构基础仍然不清楚，主要是因为使用同步辐射生长高质量晶体进行结构测定存在困难。通过应用最近在X射线自由电子激光上开发的串联飞秒晶体学方法，我们成功地在2.9埃分辨率下确定了与选择性拮抗剂ZD7155复合的人AT(1)R的室温晶体结构。AT(1)R-ZD7155复合结构揭示了AT(1)R的关键结构特征以及ZD7155结合的关键相互作用。将临床使用的ARB对接至AT(1)R结构的模拟进一步阐明了这些抗高血压药物的共同和不同结合模式。因此，我们的结果为AT(1)R结构-功能关系和基于结构的药物设计提供了基本见解。
