Understanding of G protein-coupled odorant receptors function

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Abstract: The strategy used by our brain to detect and make sense of its volatile environment is olfaction. Olfactory perception begins with the interaction of odorants with odorant receptors (OR) expressed by olfactory sensory neurons (OSN). Odor recognition follows a combinatorial coding scheme, where one OR can be activated by a set of odorants and one odorant can activate a combination of ORs. Through such combinatorial coding, organisms can detect and discriminate between a myriad of volatile odor molecules. Thus, an odor at a given concentration can be described by an activation pattern of ORs, which is specific to each odor. In that sense, cracking the mechanisms that the brain uses to perceive odor requires the understanding odorant-OR interactions. In the G protein coupled receptor family (GPCR), the rhodopsin class contains the subfamily associated with odor perception, the ORs. GPCRs are essential in pharmacology since they represent a third of the drug target. Their structural determination, such as for the beta 2 adrenergic receptor, has helped understanding how drugs interact with their target. Despite ORs represent nearly a half of the GPCR family with 400 different members in humans, none has been structurally elucidated, notably due to their challenging expression in cell systems. Theoretical structures of ORs built by homology with non-olfactory GPCRs are currently state-of-the-art to gain fundamental knowledge on OR function. Such models will strongly benefit from an OR structure template. Using the diversity of the OR repertoire, I will design new odorant receptors called "consensus ORs". Their expression and mechanisms of activation and inhibition will be comparable to structurally elucidated non-olfactory GPCR. I will thus obtain a performant set of ORs, which will be subjected to in silico and in vitro approaches. This transdisciplinary research strategy will include molecular modeling, functional assays, site-directed mutagenesis, protein production and purification. It is of central importance to identify general mechanisms governing the function of ORs and GPCRs in general. It will allow describing odorant-OR interaction with unprecedented level of details, as well as understanding the strategy our brain uses to perceive its olfactory environment.