What could be the cause of olfactory disorders? And is the peripheral olfactory system involved? Odor perception is decoded first at the odorant receptors (ORs) level, which belongs to the large family of G protein-coupled receptors and more particularly to the rhodopsin-like family, also called class A. Understanding how ORs could be involved in olfactory disorder requires knowing how they bind odorants and how these molecular machines convert an agonist binding into a neuronal signal. Here, we study this sub-family of G protein-coupled receptors at the molecular level thanks to recent advances in their structural elucidation. We used the diversity of the odorant receptor repertoire to create new optimized synthetic receptors based on their consensus sequences. Using these consensus ORs cases, we study the role of amino acids in their expression through molecular modeling, site-directed mutagenesis, and flow cytometry. Their functionality is also assessed by in vitro assays. We then developed a protocol to produce and purify the most promising ORs which allowed us to obtain the very first structural elucidation of diverse members of the mammalian OR family. This research is crucial, not only to understand the strategy of our brain to perceive its olfactory environment but also to identify general mechanisms governing the function of ORs.
This work was funded by the National Institutes of Health (NIH) (K99DC018333 - CAdM; R01DC020353 - HM, NV, AM)