1. Biochemistry and Chemical Biology
  2. Structural Biology and Molecular Biophysics
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Allosteric modulation in monomers and oligomers of a G protein-coupled receptor

  1. Rabindra V Shivnaraine  Is a corresponding author
  2. Brendan Kelly
  3. Krishana S Sankar
  4. Dar'ya S Redka
  5. Yi Rang Han
  6. Fei Huang
  7. Gwendolynne Elmslie
  8. Daniel Pinto
  9. Yuchong Li
  10. Jonathan V Rocheleau
  11. Claudiu C Gradinaru
  12. John Ellis
  13. James W Wells
  1. Stanford University School of Medicine, United States
  2. Stanford University, United States
  3. University of Toronto, Canada
  4. Hershey Medical Center, United States
Research Article
  • Cited 18
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Cite this article as: eLife 2016;5:e11685 doi: 10.7554/eLife.11685

Abstract

The M2 muscarinic receptor is the prototypic model of allostery in GPCRs, yet the molecular and the supramolecular determinants of such effects are unknown. Monomers and oligomers of the M2 muscarinic receptor therefore have been compared to identify those allosteric properties that are gained in oligomers. Allosteric interactions were monitored by means of a FRET-based sensor of conformation at the allosteric site and in pharmacological assays involving mutants engineered to preclude intramolecular effects. Electrostatic, steric, and conformational determinants of allostery at the atomic level were examined in molecular dynamics simulations. Allosteric effects in monomers were exclusively negative and derived primarily from intramolecular electrostatic repulsion between the allosteric and orthosteric ligands. Allosteric effects in oligomers could be positive or negative, depending upon the allosteric-orthosteric pair, and they arose from interactions within and between the constituent protomers. The complex behavior of oligomers is characteristic of muscarinic receptors in myocardial preparations.

Article and author information

Author details

  1. Rabindra V Shivnaraine

    Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, United States
    For correspondence
    rvshiv@stanford.edu
    Competing interests
    The authors declare that no competing interests exist.
  2. Brendan Kelly

    Department of Computer Science, Stanford University, Stanford, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Krishana S Sankar

    Department of Physiology, University of Toronto, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
  4. Dar'ya S Redka

    Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
  5. Yi Rang Han

    Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
  6. Fei Huang

    Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
  7. Gwendolynne Elmslie

    Departments of Psychiatry and Pharmacology, Hershey Medical Center, Hershey, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Daniel Pinto

    Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
  9. Yuchong Li

    Department of Physics, University of Toronto, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
  10. Jonathan V Rocheleau

    Department of Physiology, University of Toronto, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
  11. Claudiu C Gradinaru

    Department of Physics, University of Toronto, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
  12. John Ellis

    Departments of Psychiatry and Pharmacology, Hershey Medical Center, Hershey, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. James W Wells

    Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.

Reviewing Editor

  1. Werner Kühlbrandt, Max Planck Institute of Biophysics, Germany

Publication history

  1. Received: September 17, 2015
  2. Accepted: April 30, 2016
  3. Accepted Manuscript published: May 6, 2016 (version 1)
  4. Version of Record published: June 9, 2016 (version 2)

Copyright

© 2016, Shivnaraine et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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