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

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.