Conformational rearrangement during activation of a metabotropic glutamate receptor

Nat Chem Biol. 2021 Mar;17(3):291-297. doi: 10.1038/s41589-020-00702-5. Epub 2021 Jan 4.

Abstract

G protein-coupled receptors (GPCRs) relay information across cell membranes through conformational coupling between the ligand-binding domain and cytoplasmic signaling domain. In dimeric class C GPCRs, the mechanism of this process, which involves propagation of local ligand-induced conformational changes over 12 nm through three distinct structural domains, is unknown. Here, we used single-molecule FRET and live-cell imaging and found that metabotropic glutamate receptor 2 (mGluR2) interconverts between four conformational states, two of which were previously unknown, and activation proceeds through the conformational selection mechanism. Furthermore, the conformation of the ligand-binding domains and downstream domains are weakly coupled. We show that the intermediate states act as conformational checkpoints for activation and control allosteric modulation of signaling. Our results demonstrate a mechanism for activation of mGluRs where ligand binding controls the proximity of signaling domains, analogous to some receptor kinases. This design principle may be generalizable to other biological allosteric sensors.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Regulation
  • Amino Acids / pharmacology
  • Binding Sites
  • Biosensing Techniques
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacology
  • Cyclopropanes / pharmacology
  • Fluorescence Resonance Energy Transfer
  • Gene Expression
  • Genetic Vectors / chemistry
  • Genetic Vectors / metabolism
  • Glutamic Acid / chemistry*
  • Glutamic Acid / pharmacology
  • Glycine / analogs & derivatives
  • Glycine / pharmacology
  • HEK293 Cells
  • Humans
  • Ligands
  • Models, Molecular
  • Protein Binding
  • Protein Conformation, alpha-Helical
  • Protein Conformation, beta-Strand
  • Protein Interaction Domains and Motifs
  • Protein Multimerization / drug effects
  • Receptors, Metabotropic Glutamate / agonists
  • Receptors, Metabotropic Glutamate / chemistry*
  • Receptors, Metabotropic Glutamate / genetics
  • Receptors, Metabotropic Glutamate / metabolism
  • Single Molecule Imaging

Substances

  • Amino Acids
  • Bridged Bicyclo Compounds, Heterocyclic
  • Cyclopropanes
  • LY 379268
  • Ligands
  • Receptors, Metabotropic Glutamate
  • metabotropic glutamate receptor 2
  • 2-(2,3-dicarboxycyclopropyl)glycine
  • Glutamic Acid
  • Glycine