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Title: Structural basis for selectivity and diversity in angiotensin II receptors

The angiotensin II receptors AT 1R and AT 2R serve as key components of the renin–angiotensin–aldosterone system. AT 1R has a central role in the regulation of blood pressure, but the function of AT 2R is unclear and it has a variety of reported effects. To identify the mechanisms that underlie the differences in function and ligand selectivity between these receptors, here we report crystal structures of human AT 2R bound to an AT 2R-selective ligand and to an AT 1R/AT 2R dual ligand, capturing the receptor in an active-like conformation. Unexpectedly, helix VIII was found in a non-canonical position, stabilizing the active-like state, but at the same time preventing the recruitment of G proteins or β-arrestins, in agreement with the lack of signalling responses in standard cellular assays. Structure–activity relationship, docking and mutagenesis studies revealed the crucial interactions for ligand binding and selectivity. Finally, our results thus provide insights into the structural basis of the distinct functions of the angiotensin receptors, and may guide the design of new selective ligands.
Authors:
 [1] ;  [2] ;  [3] ;  [2] ;  [2] ;  [2] ;  [2] ;  [4] ;  [5] ;  [5] ;  [6] ;  [7] ;  [3] ;  [8] ;  [8] ;  [5] ;  [5] ;  [9] ;  [9] ;  [4] more »;  [9] ;  [4] ;  [5] ;  [2] ;  [2] ;  [2] « less
  1. Univ. of Southern California, Los Angeles, CA (United States); Zhejiang Univ., Zhejiang (China)
  2. Univ. of Southern California, Los Angeles, CA (United States)
  3. SLAC National Accelerator Lab., Menlo Park, CA (United States)
  4. Merck & Co., Inc., Kenilworth, NJ (United States)
  5. Merck & Co., Inc., West Point, PA (United States)
  6. Univ. of Hamburg, Hamburg (Germany); Deutsches Elektronen-Synchrotron (DESY), Hamburg (Germany)
  7. Deutsches Elektronen-Synchrotron (DESY), Hamburg (Germany)
  8. Arizona State Univ., Tempe, AZ (United States)
  9. Merck & Co., Inc., North Wales, PA (United States)
Publication Date:
Grant/Contract Number:
AC02-76SF00515
Type:
Accepted Manuscript
Journal Name:
Nature (London)
Additional Journal Information:
Journal Name: Nature (London); Journal Volume: 544; Journal Issue: 7650; Journal ID: ISSN 0028-0836
Publisher:
Nature Publishing Group
Research Org:
SLAC National Accelerator Lab. (SLAC), Menlo Park, CA (United States)
Sponsoring Org:
USDOE
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; 59 BASIC BIOLOGICAL SCIENCES
OSTI Identifier:
1361139