SMBp Group Meeting: Josefina del Marmol

Thursday Apr 7, 2022, 12:15 PM → 1:15 PM America/New_York

3rd Floor Classroom/3-Flatiron Institute (162 5th Avenue)

Speaker: Josefina del Marmol

Topic: A structural approach to the puzzle of olfaction

Abstract: Animals detect and discriminate an enormous diversity of odorants by relying on the combinatorial activation of large families of olfactory receptors. A key feature of this sensory strategy is that olfactory receptors exhibit a wide array of ligand specificities, with some receptors being activated by multiple odorants and others responding to a single chemical compound. How olfactory receptors achieve this remarkable flexibility in ligand binding remains elusive, as the isolation and structural characterization of olfactory receptors has presented a decades-long technical challenge. In this talk I will present the first structural and mechanistic characterization of odor recognition by an olfactory receptor. Using cryo-electron microscopy we elucidated the structure of an insect olfactory receptor, alone and in complex with two agonists—the odorant eugenol and the insect repellent DEET. These structures, combined with functional studies, reveal that both ligands bind to a common binding site through hydrophobic, non-directional interactions distributed throughout the binding pocket. Mutation of individual residues lining the binding pocket predictably altered this receptor’s sensitivity to eugenol and DEET and broadly reconfigured the receptor’s tuning, supporting a model in which diverse odorants share the same structural determinants for binding. These studies provide a structural framework to uncover the molecular principles that govern the detection of the vast chemical world. In addition, this work lays the foundations for future work aimed at understanding how evolution shapes OR tuning to enable the emergence of species-specific olfactory adaptations.