Agonists and allosteric modulators promote signaling from different metabotropic glutamate receptor 5 conformations

Cell Rep. 2021 Aug 31;36(9):109648. doi: 10.1016/j.celrep.2021.109648.


Metabotropic glutamate receptors (mGluRs) are dimeric G-protein-coupled receptors activated by the main excitatory neurotransmitter, L-glutamate. mGluR activation by agonists binding in the venus flytrap domain is regulated by positive (PAM) or negative (NAM) allosteric modulators binding to the 7-transmembrane domain (7TM). We report the cryo-electron microscopy structures of fully inactive and intermediate-active conformations of mGlu5 receptor bound to an antagonist and a NAM or an agonist and a PAM, respectively, as well as the crystal structure of the 7TM bound to a photoswitchable NAM. The agonist induces a large movement between the subunits, bringing the 7TMs together and stabilizing a 7TM conformation structurally similar to the inactive state. Using functional approaches, we demonstrate that the PAM stabilizes a 7TM active conformation independent of the conformational changes induced by agonists, representing an alternative mode of mGlu activation. These findings provide a structural basis for different mGluR activation modes.

Keywords: G-protein-coupled receptors; X-ray crystallography; allosteric modulators; cryo-EM; glutamate; metabotropic glutamate receptor 5; photochromic ligands; signal transduction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cryoelectron Microscopy
  • Crystallography, X-Ray
  • Excitatory Amino Acid Agonists / metabolism
  • Excitatory Amino Acid Agonists / pharmacology*
  • Excitatory Amino Acid Antagonists / metabolism
  • Excitatory Amino Acid Antagonists / pharmacology*
  • HEK293 Cells
  • Humans
  • Models, Molecular
  • Protein Binding
  • Protein Interaction Domains and Motifs
  • Protein Stability
  • Protein Subunits
  • Receptor, Metabotropic Glutamate 5 / agonists*
  • Receptor, Metabotropic Glutamate 5 / antagonists & inhibitors*
  • Receptor, Metabotropic Glutamate 5 / metabolism
  • Receptor, Metabotropic Glutamate 5 / ultrastructure
  • Signal Transduction / drug effects*
  • Structure-Activity Relationship


  • Excitatory Amino Acid Agonists
  • Excitatory Amino Acid Antagonists
  • GRM5 protein, human
  • Protein Subunits
  • Receptor, Metabotropic Glutamate 5