@article{d68a8751f0224a0d81a933b671f42662,
title = "Structure of the angiotensin receptor revealed by serial femtosecond crystallography",
abstract = "Angiotensin II type 1 receptor (AT1R) 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 AT1R blockers (ARBs), the structural basis for AT1R 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 AT1R in complex with its selective antagonist ZD7155 at 2.9-{\AA} resolution. The AT1R-ZD7155 complex structure revealed key structural features of AT1R and critical interactions for ZD7155 binding. Docking simulations of the clinically used ARBs into the AT1R structure further elucidated both the common and distinct binding modes for these anti-hypertensive drugs. Our results thereby provide fundamental insights into AT1R structure-function relationship and structure-based drug design.",
author = "Haitao Zhang and Hamiyet Unal and Cornelius Gati and Han, {Gye Won} and Wei Liu and Nadia Zatsepin and Daniel James and Dingjie Wang and Garrett Nelson and Uwe Weierstall and Sawaya, {Michael R.} and Qingping Xu and Marc Messerschmidt and Williams, {Garth J.} and S{\'e}bastien Boutet and Yefanov, {Oleksandr M.} and White, {Thomas A.} and Chong Wang and Andrii Ishchenko and Tirupula, {Kalyan C.} and Russell Desnoyer and Jesse Coe and Conrad, {Chelsie E.} and Petra Fromme and Stevens, {Raymond C.} and Vsevolod Katritch and Karnik, {Sadashiva S.} and Vadim Cherezov",
note = "Funding Information: This work was supported in parts by the NIH grants R01 GM108635 (V.C.), U54 GM094618 (target GPCR-11) (V.K., V.C., R.C.S.), P41 GM103393 (S.B.), R01 HL57470 (S.S.K.), R01 HL115964 (S.S.K.), U54 GM094599 (P.F.), R01 GM095583 (P.F.), U54 GM094586 (Q.X.), and National Research Service award HL007914 (H.U.). Further support was provided by the NSF BioXFEL Science and Technology center grant 1231306 (P.F., U.W, G.N.); the Helmholtz Gemeinschaft , the DFG Cluster of Excellence “Center for Ultrafast Imaging” ; the BMBF project FKZ 05K12CH1 (C.G., O.M.Y., T.A.W.); the PIER Helmholtz Graduate School and the Helmholtz Association (C.G.); and the Chinese 1000 Talent Program (R.C.S.). Parts of this research were carried out at the LCLS, a National User Facility operated by Stanford University on behalf of the U.S. Department of Energy, Office of Basic Energy Sciences, and at the GM/CA CAT of the Argonne Photon Source, Argonne National Laboratory. We thank J. Velasquez for help with molecular biology; T. Trinh and M. Chu for help with baculovirus expression; M. Metz, D. Oberthuer, A. Barty, S. Basu, and R. Fromme for help with the XFEL data collection and analysis, and R. Miller, K. Kadyshevskaya, and A. Walker for assistance with manuscript preparation. We are grateful to J. Spence and H. Chapman for their encouragement and support. Publisher Copyright: {\textcopyright} 2015 Elsevier Inc.",
year = "2015",
month = may,
day = "7",
doi = "10.1016/j.cell.2015.04.011",
language = "English (US)",
volume = "161",
pages = "833--844",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "4",
}