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Cell. 2015 May 7;161(4):833-44. doi: 10.1016/j.cell.2015.04.011. Epub 2015 Apr 23.

Structure of the Angiotensin receptor revealed by serial femtosecond crystallography.

Author information

1
Department of Biological Sciences, Bridge Institute, University of Southern California, Los Angeles, CA 90089, USA.
2
Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
3
Center for Free Electron Laser Science, Deutsches Elektronen-Synchrotron DESY, 22607 Hamburg, Germany.
4
Department of Chemistry, Bridge Institute, University of Southern California, Los Angeles, CA 90089 USA.
5
Department of Chemistry and Biochemistry, Center for Applied Structural Discovery at the Biodesign Institute, Arizona State University, Tempe, AZ 85287, USA.
6
Department of Physics, Arizona State University, Tempe, AZ 85287, USA.
7
Department of Chemistry and Biochemistry, the UCLA-DOE Institute for Genomics and Proteomics, University of California, Los Angeles, CA 90095, USA.
8
Joint Center for Structural Genomics, Stanford Synchrotron Radiation Light Source, SLAC National Accelerator Laboratory, Menlo Park, CA 94025, USA.
9
BioXFEL Science and Technology Center, Buffalo, NY 14203, USA.
10
Linac Coherent Light Source, SLAC National Accelerator Laboratory, Menlo Park, CA 94025, USA.
11
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA.
12
Department of Biological Sciences, Bridge Institute, University of Southern California, Los Angeles, CA 90089, USA; Department of Chemistry, Bridge Institute, University of Southern California, Los Angeles, CA 90089 USA; iHuman Institute, ShanghaiTech University, Shanghai, 201210 China.
13
Department of Chemistry, Bridge Institute, University of Southern California, Los Angeles, CA 90089 USA. Electronic address: cherezov@usc.edu.

Abstract

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.

PMID:
25913193
PMCID:
PMC4427029
DOI:
10.1016/j.cell.2015.04.011
[Indexed for MEDLINE]
Free PMC Article

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