Poster Abstract: Marc El Hasbany

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Deciphering the molecular basis for activation and inhibition of olfactory receptors.

Marc El Hasbany;1Chulwon Choi;2 Marie-Charlotte Dumargne;3 Romain Barrès;3 Hee-Jung Choi;2 Jérémie Topin1

  1. Institut de Chimie de Nice – UMR CNRS 7272, Université-Côte d’Azur-CNRS, 28 avenue Valrose, Nice, France;

2) Department of Biological Sciences, Seoul National University, Seoul, 08826, South Korea ;

  1. Institut de pharmacologie moléculaire et cellulaire – UMR CNRS 7275, 660 route des lucioles, Sophia Antipolis, France.
Olfactory receptors (ORs) are part of the largest family of G protein-coupled receptors and constitute the molecular basis for the detection and discrimination of a vast chemical space of volatile compounds. ORs function through a combinatorial mechanism, meaning that a single odorant can activate multiple receptors, while a single receptor can respond to structurally diverse ligands. Beyond their sensory role, select ORs are ectopically expressed in non-olfactory tissues; Olfr412, for instance, is expressed in spermatozoa and participates in chemotaxis, highlighting the broader physiological relevance of this receptor family. Despite significant advances in the field regarding the molecular mechanisms of odorant recognition and receptor activation, receptor inhibition remains poorly understo od.

This study integrates computational modeling with experimental validation to decipher and further understand the molecular determinants of OR activation and inhibition. Olfr412, the ectopically expressed OR in mice, bound with different types of odorants served as the selected model systems. We combine molecular docking and simulations to characterize agonist, and inverse agonist binding at the atomic level. Comparative analysis of OR-agonist and OR-inverse agonist complexes reveals differences in receptor-ligand interactions highlighting the differences between activation and inhibition. Additionally, virtual screening was performed on a dataset of odorants collected from the M2OR database to identify other potential agonists and inverse agonists. The selected odorants were subsequently tested experimentally to validate their effect on OR activity. Furthermore, Umbrella Sampling was employed to map the translocation pathways of odorants through the Olfr 412.

Collectively, this work deepens our understanding of OR activation and inhibition at the molecular level, with implications for both their sensory and ectopic function, enabling the design of modula tors.