Structure of a class C GPCR metabotropic glutamate receptor 1 bound to an allosteric modulator

Science. 2014 Apr 4;344(6179):58-64. doi: 10.1126/science.1249489. Epub 2014 Mar 6.

Abstract

The excitatory neurotransmitter glutamate induces modulatory actions via the metabotropic glutamate receptors (mGlus), which are class C G protein-coupled receptors (GPCRs). We determined the structure of the human mGlu1 receptor seven-transmembrane (7TM) domain bound to a negative allosteric modulator, FITM, at a resolution of 2.8 angstroms. The modulator binding site partially overlaps with the orthosteric binding sites of class A GPCRs but is more restricted than most other GPCRs. We observed a parallel 7TM dimer mediated by cholesterols, which suggests that signaling initiated by glutamate's interaction with the extracellular domain might be mediated via 7TM interactions within the full-length receptor dimer. A combination of crystallography, structure-activity relationships, mutagenesis, and full-length dimer modeling provides insights about the allosteric modulation and activation mechanism of class C GPCRs.

Publication types

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

MeSH terms

  • Allosteric Regulation
  • Allosteric Site
  • Amino Acid Sequence
  • Benzamides / chemistry*
  • Benzamides / metabolism*
  • Binding Sites
  • Cholesterol
  • Crystallography, X-Ray
  • Humans
  • Hydrophobic and Hydrophilic Interactions
  • Ligands
  • Models, Molecular
  • Molecular Sequence Data
  • Mutation
  • Protein Conformation
  • Protein Multimerization
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Receptors, Metabotropic Glutamate / chemistry*
  • Receptors, Metabotropic Glutamate / metabolism*
  • Structure-Activity Relationship
  • Thiazoles / chemistry*
  • Thiazoles / metabolism*

Substances

  • 4-fluoro-N-(4-(6-(isopropylamino)pyrimidin-4-yl)-1,3-thiazol-2-yl)-N-methylbenzamide
  • Benzamides
  • Ligands
  • Receptors, Metabotropic Glutamate
  • Thiazoles
  • metabotropic glutamate receptor type 1
  • Cholesterol

Associated data

  • PDB/4OR2