Allosteric modulation in monomers and oligomers of a G protein-coupled receptor
- Stanford University School of Medicine, United States
- Stanford University, United States
- University of Toronto, Canada
- Hershey Medical Center, United States
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
Reviewing Editor
- Werner Kühlbrandt, Max Planck Institute of Biophysics, Germany
Version history
- Received: September 17, 2015
- Accepted: April 30, 2016
- Accepted Manuscript published: May 6, 2016 (version 1)
- 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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Allosteric modulation in monomers and oligomers of a G protein-coupled receptor
eLife 5:e11685.
https://doi.org/10.7554/eLife.11685
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