Mammalian class I odorant receptors exhibit a conserved vestibular-binding pocket
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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.
KeywordsOlfactory GPCR Molecular modeling Mechanism Binding Mutant
This work is supported by Grants from the National Institute on Deafness and Other Communication Disorders, National Institute of Health Grants DC014423 and DC016224, National Science Foundation (NSF) Grants 1515801 and 1556207 (to H.M.) and from Agence Nationale de la Recherche (Neurolf project to J.G.) as part of NSF/NIH/ANR Collaborative Research in Computational Neuroscience and from the Fondation Roudnitska under the aegis of Fondation de France to C.B. This work is also funded by Université Côte d’Azur IDEX JEDI to J.G. C.B. thanks GIRACT and the GEN foundation for a Ph.D. bursary.
CB: performed numerical modeling, analyzed the data, and wrote the paper. CADM: performed in vitro experiments and analyzed the data. JT: performed numerical modeling and analyzed the data. MD: performed in vitro experiments. HM: conceived the study and analyzed the data. JG: conceived the study, analyzed the data, and wrote the paper.
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