Structure of the Angiotensin receptor revealed by serial femtosecond crystallography.
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.
Department of Biological Sciences, Bridge Institute, University of Southern California, Los Angeles, CA 90089, USA.
Haitao
H
Zhang
Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
Hamiyet
H
Unal
Center for Free Electron Laser Science, Deutsches Elektronen-Synchrotron DESY, 22607 Hamburg, Germany.
Cornelius
C
Gati
Department of Chemistry, Bridge Institute, University of Southern California, Los Angeles, CA 90089 USA.
Gye Won
GW
Han
Department of Chemistry and Biochemistry, Center for Applied Structural Discovery at the Biodesign Institute, Arizona State University, Tempe, AZ 85287, USA.
Wei
W
Liu
Department of Physics, Arizona State University, Tempe, AZ 85287, USA.
Nadia A
NA
Zatsepin
Department of Physics, Arizona State University, Tempe, AZ 85287, USA.
Daniel
D
James
Department of Physics, Arizona State University, Tempe, AZ 85287, USA.
Dingjie
D
Wang
Department of Physics, Arizona State University, Tempe, AZ 85287, USA.
Garrett
G
Nelson
Department of Physics, Arizona State University, Tempe, AZ 85287, USA.
Uwe
U
Weierstall
Department of Chemistry and Biochemistry, the UCLA-DOE Institute for Genomics and Proteomics, University of California, Los Angeles, CA 90095, USA.
Michael R
MR
Sawaya
Joint Center for Structural Genomics, Stanford Synchrotron Radiation Light Source, SLAC National Accelerator Laboratory, Menlo Park, CA 94025, USA.
Qingping
Q
Xu
BioXFEL Science and Technology Center, Buffalo, NY 14203, USA.
Marc
M
Messerschmidt
Linac Coherent Light Source, SLAC National Accelerator Laboratory, Menlo Park, CA 94025, USA.
Garth J
GJ
Williams
Linac Coherent Light Source, SLAC National Accelerator Laboratory, Menlo Park, CA 94025, USA.
Sébastien
S
Boutet
Center for Free Electron Laser Science, Deutsches Elektronen-Synchrotron DESY, 22607 Hamburg, Germany.
Oleksandr M
OM
Yefanov
Center for Free Electron Laser Science, Deutsches Elektronen-Synchrotron DESY, 22607 Hamburg, Germany.
Thomas A
TA
White
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA.
Chong
C
Wang
Department of Chemistry, Bridge Institute, University of Southern California, Los Angeles, CA 90089 USA.
Andrii
A
Ishchenko
Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
Kalyan C
KC
Tirupula
Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
Russell
R
Desnoyer
Department of Chemistry and Biochemistry, Center for Applied Structural Discovery at the Biodesign Institute, Arizona State University, Tempe, AZ 85287, USA.
Jesse
J
Coe
Department of Chemistry and Biochemistry, Center for Applied Structural Discovery at the Biodesign Institute, Arizona State University, Tempe, AZ 85287, USA.
Chelsie E
CE
Conrad
Department of Chemistry and Biochemistry, Center for Applied Structural Discovery at the Biodesign Institute, Arizona State University, Tempe, AZ 85287, USA.
Petra
P
Fromme
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.
Raymond C
RC
Stevens
Department of Biological Sciences, Bridge Institute, University of Southern California, Los Angeles, CA 90089, USA.
Vsevolod
V
Katritch
Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
Sadashiva S
SS
Karnik
Department of Chemistry, Bridge Institute, University of Southern California, Los Angeles, CA 90089 USA. Electronic address: cherezov@usc.edu.
Vadim
V
Cherezov
D000595:Amino Acid Sequence; D047228:Angiotensin II Type 1 Receptor Blockers / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D006801:Humans; D008969:Molecular Sequence Data; D016296:Mutagenesis; D009287:Naphthyridines / Q000737:chemistry / Q000494:pharmacology; D044140:Receptor, Angiotensin, Type 1 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment
C544065:AGTR1 protein, human; D047228:Angiotensin II Type 1 Receptor Blockers; D009287:Naphthyridines; D044140:Receptor, Angiotensin, Type 1; C095905:ZD 7155