Major ligand-induced rearrangement of the heptahelical domain interface in a GPCR dimer

Nat Chem Biol. 2015 Feb;11(2):134-40. doi: 10.1038/nchembio.1711. Epub 2014 Dec 15.

Abstract

G protein-coupled receptors (GPCRs) are major players in cell communication. Although they form functional monomers, increasing evidence indicates that GPCR dimerization has a critical role in cooperative phenomena that are important for cell signal integration. However, the structural bases of these phenomena remain elusive. Here, using well-characterized receptor dimers, the metabotropic glutamate receptors (mGluRs), we show that structural changes at the dimer interface are linked to receptor activation. We demonstrate that the main dimer interface is formed by transmembrane α helix 4 (TM4) and TM5 in the inactive state and by TM6 in the active state. This major change in the dimer interface is required for receptor activity because locking the TM4-TM5 interface prevents activation by agonist, whereas locking the TM6 interface leads to a constitutively active receptor. These data provide important information on the activation mechanism of mGluRs and improve our understanding of the structural basis of the negative cooperativity observed in these GPCR dimers.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alanine / genetics
  • Animals
  • COS Cells
  • Chlorocebus aethiops
  • Cysteine / genetics
  • HEK293 Cells
  • Humans
  • Ligands
  • Models, Molecular
  • Mutagenesis, Site-Directed
  • Protein Binding
  • Protein Multimerization*
  • Protein Structure, Tertiary
  • Protein Subunits
  • Rats
  • Receptor, Metabotropic Glutamate 5 / agonists
  • Receptor, Metabotropic Glutamate 5 / chemistry
  • Receptor, Metabotropic Glutamate 5 / genetics
  • Receptors, GABA-B / chemistry
  • Receptors, GABA-B / genetics
  • Receptors, GABA-B / metabolism
  • Receptors, Metabotropic Glutamate / agonists
  • Receptors, Metabotropic Glutamate / chemistry*
  • Receptors, Metabotropic Glutamate / genetics
  • Transcriptional Activation
  • Transfection

Substances

  • GABA type B receptor, subunit 1
  • Grm5 protein, rat
  • Ligands
  • Protein Subunits
  • Receptor, Metabotropic Glutamate 5
  • Receptors, GABA-B
  • Receptors, Metabotropic Glutamate
  • metabotropic glutamate receptor 2
  • metabotropic glutamate receptor type 1
  • Cysteine
  • Alanine