Mammalian class I odorant receptors exhibit a conserved vestibular-binding pocket

• DOI: 10.1007/s00018-018-2996-4
• Publication Date: 2018-12-31T22:14:49Z
• Authors: Caroline Bushdid; Claire A. de March; Jérémie Topin; Matthew Do; Hiroaki Matsunami; Jérôme Golebiowski
• Keywords: DYNAMICS; EXPRESSION; Models, Molecular; 0301 basic medicine; 570; Amino Acid Motifs; Molecular modeling; Molecular Dynamics Simulation; Receptors, Odorant; ACTIVATION; 03 medical and health sciences; GPCR; 616; Humans; MULTIGENE FAMILY; SIGNATURES; Conserved Sequence; 0303 health sciences; Binding Sites; Mutant; SITE; Binding; GENE SUPERFAMILY; OLFACTORY RECEPTOR; Mechanism; Olfactory

Odorant receptors represent the largest family of mammalian G protein-coupled receptors. Phylogenetically, they are split into two classes (I and II). By analyzing the entire subclass I odorant receptors sequences, we identified two class I-specific and highly conserved motifs. These are predicted to face each other at the extra-cellular portion of the transmembrane domain, forming a vestibular site at the entrance to the orthosteric-binding cavity. Molecular dynamics simulation combined with site-directed mutagenesis and in vitro functional assays confirm the functional role of this vestibular site in ligand-driven activation. Mutations at this part of the receptor differentially affect the receptor response to four agonists. Since this vestibular site is involved in ligand recognition, it could serve ligand design that targets specifically this sub-genome of mammalian odorant receptors.