G Protein-Coupled Odorant Receptor function – WhoNose

To evolve in their volatile environment, mammals constantly call on their sense of smell. Odor can be seen as a chemical signal converted by the brain into an electrical signal itself translated into perceptions and emotions. This simplistic view is not representative of the molecular puzzle involved. The beginning of this cascade of events is itself a challenge to understand and happens at the level of the interaction of odorants with our odorant receptors (OR), carried by the olfactory sensory neurons in the olfactory mucosa. It is now well established that OR, apart from being essential in the perception of odors, play a role in developmental & physiological processes. They have been found in other tissues such as lung/prostate cancer, cardiomyocytes, and kidney tissue cells or primary melanocytes suggesting a broader action and a strong potential for becoming therapeutic targets. The exact molecular mechanism by which they accomplish their function is very sparse and requires information at the atomic scale which is currently largely missing. They are an understudied protein family despite representing nearly half of the large G Protein-Coupled Receptor (GPCR) family members, mainly because there are, until very recently, no published experimental structures of mammalian OR. The main barrier to tackling this challenge is the lack of OR expression at the membrane of conventional eukaryotic and prokaryotic cell models currently used for protein production. This project aims to provide an original in cellulo/in silico solution to address this unmet need. As a study model, I will rely on a recent breakthrough whereby we successfully designed "consensus” OR sequences. This stabilization strategy, well established for other protein families but not GPCR and distinct from the classical thermostabilization, states that a conserved amino acid at a certain position in a protein family is contributing more to the function of the family than a random amino acid. The "consensus" OR showed expression levels comparable to structurally elucidated non-olfactory GPCRs. In combination with the recent progress in protein structural elucidation methods, it allowed us to solve the first mammalian OR experimental structures. We now know that OR possess unique structures within the GPCR family that probably serve their function. However, the parameters giving to the "consensus" OR their high cell surface expression or a complete description of OR dynamic ligand binding and activation mechanism remain to be established. Using the highly functional "consensus" OR and these first experimental OR structures, WhoNose will first establish a computationally assisted path to understand the key sequence features controlling OR expression and obtain high-level expression of OR in conventional cell lines. Second, we will explore their pharmacology and activation mechanism which are unique within the GPCR family. The project will provide new knowledge on the general mechanisms governing these essential receptors’ function, unlock further transdisciplinary research projects, and will find multiple applications in the food, perfume, cosmetics, and health sectors.