Conserved Residues Control Activation of Mammalian G Protein-Coupled Odorant Receptors

J Am Chem Soc. 2015 Jul 8;137(26):8611-8616. doi: 10.1021/jacs.5b04659. Epub 2015 Jun 29.


Odorant receptor (OR) genes and proteins represent more than 2% of our genome and 4% of our proteome and constitute the largest subgroup of G protein-coupled receptors (GPCRs). The mechanism underlying OR activation remains poorly understood, as they do not share some of the highly conserved motifs critical for activation of non-olfactory GPCRs. By combining site-directed mutagenesis, heterologous expression, and molecular dynamics simulations that capture the conformational change of constitutively active mutants, we tentatively identified crucial residues for the function of these receptors using the mouse MOR256-3 (Olfr124) as a model. The toggle switch for sensing agonists involves a highly conserved tyrosine residue in helix VI. The ionic lock is located between the "DRY" motif in helix III and a positively charged "R/K" residue in helix VI. This study provides an unprecedented model that captures the main mechanisms of odorant receptor activation.

Publication types

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

MeSH terms

  • Amino Acid Motifs
  • Amino Acid Sequence
  • Animals
  • Conserved Sequence
  • Mice
  • Molecular Dynamics Simulation
  • Molecular Sequence Data
  • Mutagenesis, Site-Directed
  • Mutation
  • Protein Binding
  • Protein Conformation
  • Receptors, G-Protein-Coupled / chemistry*
  • Receptors, Odorant / chemistry*
  • Sequence Homology, Amino Acid
  • Software
  • Tyrosine / chemistry


  • Olfr124 protein, mouse
  • Receptors, G-Protein-Coupled
  • Receptors, Odorant
  • Tyrosine