2. Academic Validation
  3. Angiotensin Analogs with Divergent Bias Stabilize Distinct Receptor Conformations

Angiotensin Analogs with Divergent Bias Stabilize Distinct Receptor Conformations

  • Cell. 2019 Jan 24;176(3):468-478.e11. doi: 10.1016/j.cell.2018.12.005.
Laura M Wingler 1,  Matthias Elgeti 2,  Daniel Hilger 3,  Naomi R Latorraca 4,  Michael T Lerch 2,  Dean P Staus 1,  Ron O Dror 5,  Brian K Kobilka 6,  Wayne L Hubbell 7,  Robert J Lefkowitz 8
Affiliations

Affiliations

  • 1 Department of Medicine and Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC 27710, USA.
  • 2 Jules Stein Eye Institute and Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • 3 Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • 4 Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA; Biophysics Program, Departments of Computer Science and Structural Biology, and Institute for Computational and Mathematical Engineering, Stanford University, Stanford, CA 94305, USA.
  • 5 Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA; Biophysics Program, Departments of Computer Science and Structural Biology, and Institute for Computational and Mathematical Engineering, Stanford University, Stanford, CA 94305, USA. Electronic address: ron.dror@stanford.edu.
  • 6 Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: kobilka@stanford.edu.
  • 7 Jules Stein Eye Institute and Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: hubbellw@jsei.ucla.edu.
  • 8 Department of Medicine and Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC 27710, USA; Department of Biochemistry, Duke University Medical Center, Durham, NC 27710, USA. Electronic address: lefko001@receptor-biol.duke.edu.
PMID: 30639099 DOI: 10.1016/j.cell.2018.12.005
Abstract

"Biased" G protein-coupled receptor (GPCR) agonists preferentially activate pathways mediated by G proteins or β-arrestins. Here, we use double electron-electron resonance spectroscopy to probe the changes that ligands induce in the conformational distribution of the angiotensin II type I receptor. Monitoring distances between 10 pairs of nitroxide labels distributed across the intracellular regions enabled mapping of four underlying sets of conformations. Ligands from different functional classes have distinct, characteristic effects on the conformational heterogeneity of the receptor. Compared to angiotensin II, the endogenous agonist, agonists with enhanced Gq coupling more strongly stabilize an "open" conformation with an accessible transducer-binding site. β-arrestin-biased agonists deficient in Gq coupling do not stabilize this open conformation but instead favor two more occluded conformations. These data suggest a structural mechanism for biased ligand action at the Angiotensin Receptor that can be exploited to rationally design GPCR-targeting drugs with greater specificity of action.

Keywords

ARB; DEER; G protein-coupled receptor; GPCR; angiotensin II type 1 receptor; angiotensin receptor blocker; beta-arrestin; biased agonism; conformational selection; double electron-electron resonance spectroscopy; functional selectivity; heterotrimeric G protein; molecular dynamics simulations.

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