title: Conserved Residues Control Activation of Mammalian G Protein-Coupled Odorant Receptors.
abstract: 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.
authors.affiliation: Institute of Chemistry - Nice, UMR 7272 CNRS - University Nice - Sophia Antipolis, 06108 Nice cedex 2, France.
authors.forename: Claire A
authors.initials: CA
authors.lastname: de March
authors.affiliation: Department of Neuroscience, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Yiqun
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Mengjue J
authors.initials: MJ
authors.lastname: Ni
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Kaylin A
authors.initials: KA
authors.lastname: Adipietro
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Matsunami
authors.affiliation: Department of Neuroscience, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Minghong
authors.initials: M
authors.lastname: Ma
authors.affiliation: Institute of Chemistry - Nice, UMR 7272 CNRS - University Nice - Sophia Antipolis, 06108 Nice cedex 2, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Golebiowski
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D017124:Conserved Sequence; D051379:Mice; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D011485:Protein Binding; D011487:Protein Conformation; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry*; D018035:Receptors, Odorant / Q000737:chemistry*; D017386:Sequence Homology, Amino Acid; D012984:Software; D014443:Tyrosine / Q000737:chemistry
chemical_list: C000607539:Olfr124 protein, mouse; D043562:Receptors, G-Protein-Coupled; D018035:Receptors, Odorant; D014443:Tyrosine