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Title: Structure of the Angiotensin Receptor Revealed by Serial Femtosecond Crystallography

We report that 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 Å resolution. The AT1R-ZD7155 complex structure revealed key structural features ofAT1R and critical interactions for ZD7155 binding. Finally, 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.
Authors:
 [1] ;  [2] ;  [3] ;  [4] ;  [5] ;  [6] ;  [6] ;  [6] ;  [6] ;  [6] ;  [7] ;  [8] ;  [9] ;  [10] ;  [10] ;  [3] ;  [3] ;  [11] ;  [4] ;  [2] more »;  [2] ;  [5] ;  [5] ;  [5] ;  [12] ;  [1] ;  [2] ;  [4] « less
  1. Univ. of Southern California, Los Angeles, CA (United States). Bridge Inst., Dept. of Biological Sciences
  2. Cleveland Clinic, Cleveland, OH (United States). Lerner Research Inst., Dept. of Molecular Cardiology
  3. Deutsches Elektronen-Synchrotron (DESY), Hamburg (Germany). Center for Free-Electron Laser Science
  4. Univ. of Southern California, Los Angeles, CA (United States). Bridge Inst., Dept. of Chemistry
  5. Arizona State Univ., Tempe, AZ (United States). Center for Applied Structural Discovery at the Biodesign Inst., Dept. of Chemistry and Biochemistry
  6. Arizona State Univ., Tempe, AZ (United States). Dept. of Physics
  7. Univ. of California, Los Angeles, CA (United States). UCLA-DOE Inst. for Genomics and Proteomics, Dept. of Chemistry and Biochemistry
  8. SLAC National Accelerator Lab., Menlo Park, CA (United States). Stanford Synchrotron Radiation Lightsource (SSRL)
  9. BioXFEL Science and Technology Center, Buffalo, NY (United States)
  10. SLAC National Accelerator Lab., Menlo Park, CA (United States). Linac Coherent Light Source (LCLS)
  11. Harvard Univ., Cambridge, MA (United States). Dept. of Chemistry and Chemical Biology
  12. Univ. of Southern California, Los Angeles, CA (United States). Bridge Inst., Dept. of Biological Sciences; Univ. of Southern California, Los Angeles, CA (United States). Bridge Inst., Dept. of Chemistry; Shanghai Tech Univ., Shanghai (China). iHuman Inst.
Publication Date:
OSTI Identifier:
1194670
Grant/Contract Number:
R01 GM108635; U54 GM094618; P41 GM103393; R01 HL57470; R01 HL115964; U54 GM094599
Type:
Accepted Manuscript
Journal Name:
Cell
Additional Journal Information:
Journal Volume: 161; Journal Issue: 4; Journal ID: ISSN 0092-8674
Publisher:
Elsevier
Research Org:
SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States). Linac Coherent Light Source
Sponsoring Org:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; 59 BASIC BIOLOGICAL SCIENCES AT1R; anti-hypertensive drugs