Allosteric modulators enhance agonist efficacy by increasing the residence time of a GPCR in the active state

Nat Commun. 2021 Sep 14;12(1):5426. doi: 10.1038/s41467-021-25620-5.

Abstract

Much hope in drug development comes from the discovery of positive allosteric modulators (PAM) that display target subtype selectivity and act by increasing agonist potency and efficacy. How such compounds can allosterically influence agonist action remains unclear. Metabotropic glutamate receptors (mGlu) are G protein-coupled receptors that represent promising targets for brain diseases, and for which PAMs acting in the transmembrane domain have been developed. Here, we explore the effect of a PAM on the structural dynamics of mGlu2 in optimized detergent micelles using single molecule FRET at submillisecond timescales. We show that glutamate only partially stabilizes the extracellular domains in the active state. Full activation is only observed in the presence of a PAM or the Gi protein. Our results provide important insights on the role of allosteric modulators in mGlu activation, by stabilizing the active state of a receptor that is otherwise rapidly oscillating between active and inactive states.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Regulation / drug effects
  • Allosteric Site
  • Amino Acids / chemistry
  • Amino Acids / pharmacology
  • Biphenyl Compounds / chemistry
  • Biphenyl Compounds / pharmacology
  • Bridged Bicyclo Compounds / chemistry
  • Bridged Bicyclo Compounds / pharmacology
  • Bridged Bicyclo Compounds, Heterocyclic / chemistry
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacology
  • Catalytic Domain
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism
  • Cholesterol Esters / chemistry
  • Cholesterol Esters / pharmacology
  • Diosgenin / analogs & derivatives
  • Diosgenin / chemistry
  • Diosgenin / pharmacology
  • Disaccharides / chemistry
  • Disaccharides / pharmacology
  • Fluorescence Resonance Energy Transfer
  • Gene Expression
  • Glucosides / chemistry
  • Glucosides / pharmacology
  • Glutamic Acid / pharmacology*
  • Glycolipids / chemistry
  • Glycolipids / pharmacology
  • HEK293 Cells
  • Humans
  • Indans / chemistry
  • Indans / pharmacology
  • Micelles
  • Octoxynol / chemistry
  • Octoxynol / pharmacology
  • Protein Binding
  • Protein Conformation
  • Protein Multimerization
  • Receptors, Metabotropic Glutamate / agonists*
  • Receptors, Metabotropic Glutamate / chemistry*
  • Receptors, Metabotropic Glutamate / genetics
  • Receptors, Metabotropic Glutamate / metabolism
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Single Molecule Imaging
  • Xanthenes / chemistry
  • Xanthenes / pharmacology

Substances

  • Amino Acids
  • Biphenyl Compounds
  • Bridged Bicyclo Compounds
  • Bridged Bicyclo Compounds, Heterocyclic
  • Cholesterol Esters
  • Disaccharides
  • Glucosides
  • Glycolipids
  • Indans
  • LY 341495
  • LY 379268
  • Micelles
  • Receptors, Metabotropic Glutamate
  • Recombinant Proteins
  • Xanthenes
  • biphenyl-indanone A
  • dodecyl-beta-melibioside
  • metabotropic glutamate receptor 2
  • diosgenin glucoside
  • Glutamic Acid
  • dodecyl maltoside
  • Octoxynol
  • Diosgenin
  • eglumetad
  • cholesteryl succinate