Allosteric modulation in monomers and oligomers of a G protein-coupled receptor

Rabindra V. Shivnaraine, Brendan Kelly, Krishana S. Sankar, Dar’ya S. Redka, Yi Rang Han, Fei Huang, Gwendolynne Elmslie, Daniel Pinto, Yuchong Li, Jonathan V. Rocheleau, Claudiu C. Gradinaru, John Ellis, James W. Wells

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

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.

Original languageEnglish (US)
Article numbere11685
JournaleLife
Volume5
Issue numberMAY2016
DOIs
StatePublished - May 6 2016

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)
  • Immunology and Microbiology(all)
  • Biochemistry, Genetics and Molecular Biology(all)

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