Structures of the honeybee GABA _A RDL receptor illuminate allosteric modulation

Insect GABA _A 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 GABA _A receptors. The honeybee receptor structures may also foster the search for environmentally benign insecticides.