Insect’s olfaction : molecular caving in a co-receptor

Olfaction is critical for insects but it is also of interest in human and animal health as target for repellents strategy, especially against biting insects or for pheromone traps against pests. In winged insects, olfactory receptors (OR) form complexes composed of odorant-binding subunits (ORx) and with odorant receptor co-receptor subunits (Orco). These subunits have evolved in opposite directions, with a large divergence of the OR subunits for recognizing various ligands, while the Orco subunits were highly conserved across species and they generate an electrical signal through their cationic channel activity. Recently, the structures of an Orco and an “ancestral” OR have been solved, providing valuable information about these receptors. However, they did not reveal how the highly specific Orco ligands reach their binding site, which is supposed to be deeply embedded in a cavity within the receptor.
The current study, carried out in collaboration by researchers from the IBS Membrane Transporters group and the Nice Institute of Chemistry, combines molecular dynamics simulations and structure-function characterizations. It reveals essential features for ligand binding, such as 1) the diffusion pathway ; 2) the desolvation process of the ligand ; and 3) the agonist-binding site. Thus, their results provide new evidence for the exact location of the agonist-binding site and the detailed molecular mechanisms of translocation of the ligand. Sequence analysis of 176 Orco suggests a highly conserved mechanism across species. Those data will make easier virtual and real screening of new molecules to target insect olfaction.

Elucidation of the structural basis for ligand binding and translocation in conserved insect odorant receptor co-receptors. Pacalon J, Audic G, Magnat J, Philip M, Golebiowski J, Moreau CJ, Topin J. Nat Commun 14, 8182 (2023).

Contact : Christophe Moreau (IBS/Membrane Transporters Group)