Fine tuning of sub-millisecond conformational dynamics controls metabotropic glutamate receptors agonist efficacy

Nat Commun. 2014 Oct 17;5:5206. doi: 10.1038/ncomms6206.

Abstract

Efficient cell-to-cell communication relies on the accurate signalling of cell surface receptors. Understanding the molecular bases of their activation requires the characterization of the dynamic equilibrium between active and resting states. Here, we monitor, using single-molecule Förster resonance energy transfer, the kinetics of the reorientation of the extracellular ligand-binding domain of the metabotropic glutamate receptor (mGluR), a class C G-protein-coupled receptor. We demonstrate that most receptors oscillate between a resting- and an active-conformation on a sub-millisecond timescale. Interestingly, we demonstrate that differences in agonist efficacies stem from differing abilities to shift the conformational equilibrium towards the fully active state, rather than from the stabilization of alternative static conformations, which further highlights the dynamic nature of mGluRs and revises our understanding of receptor activation and allosteric modulation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Site
  • Catalytic Domain
  • Cell Communication
  • Fluorescence Resonance Energy Transfer
  • Guanidines / chemistry
  • HEK293 Cells
  • Humans
  • Kinetics
  • Ligands
  • Molecular Conformation
  • Mutation
  • Photons
  • Protein Binding
  • Protein Conformation
  • Protein Multimerization
  • Receptors, Metabotropic Glutamate / agonists*
  • Receptors, Metabotropic Glutamate / metabolism*
  • Signal Transduction

Substances

  • Guanidines
  • Ligands
  • Receptors, Metabotropic Glutamate
  • metabotropic glutamate receptor 2
  • benzylguanidine