Structures of the honeybee GABAA RDL receptor illuminate allosteric modulation

Insect GABAA receptors are critical insecticide targets, with all 21st-century commercial compounds acting through a single allosteric membrane site. Here we describe three ligand binding sites and the associated receptor conformations for the honeybee RDL receptor, combining cryo-EM, electrophysiology and molecular dynamics. First the conservation of the GABA site explains the absence of insect-selective orthosteric compounds. Second, the classical modulation site, occupied here by abamectin, exists in a closed-pore conformation contrasting with ivermectin-bound states in other receptors. Third, using the fungal-derived Chrodrimamin B, we resolve an unanticipated membrane modulation pocket structurally analogous yet pharmacologically opposite to a neurosteroid site in mammalian receptors. Structures also reveal the existence of an intersubunit, conformation-dependent, PIP2 lipid site. We foresee our results to be the starting point for investigations on the physiological modulation of insect GABAA receptors. The honeybee receptor structures may also foster the search for environmentally benign insecticides.