Résumé
A large share of insecticides targets insect ion channels. In particular, the GABAA RDL (resistant to dieldrin) receptor is targeted by old pore blockers or more recent allosteric modulators binding to a cavity of its transmembrane domain. Here, we describe three ligand-binding sites and the associated receptor conformations, using a combination of cryoelectron microscopy (cryo-EM), electrophysiology, and molecular dynamics. The GABA site geometry is well conserved with that of mammalian receptors, in line with the absence of orthosteric insecticide. The transmembrane modulation site, occupied here by abamectin, exists in a closed-pore conformation. We identify a second allosteric transmembrane site using a compound named chrodrimanin B. Structures also reveal the existence of a conformation-dependent PIP2 lipid site. We anticipate 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 species-specific, environmentally benign insecticides.