Recent progress in the structural study of ion channels as insecticide targets

Ion channels, many expressed in insect neural and muscular systems, have drawn huge attention as primary targets of insecticides. With the recent technical breakthroughs in structural biology, especially in cryo-electron microscopy (cryo-EM), many new high-resolution structures of ion channel targets, apo or in complex with insecticides, have been solved, shedding light on the molecular mechanism of action of the insecticides and resistance mutations. These structures also provide accurate templates for structure-based insecticide screening and rational design. This review summarizes the recent progress in the structural studies of 5 ion channel families: the ryanodine receptor (RyR), the nicotinic acetylcholine receptor (nAChR), the voltage-gated sodium channel (VGSC), the transient receptor potential (TRP) channel, and the ligand-gated chloride channel (LGCC). We address the selectivity of the channel-targeting insecticides by examining the conservation of key coordinating residues revealed by the structures. The possible resistance mechanisms are proposed based on the locations of the identified resistance mutations on the 3D structures of the target channels and their impacts on the binding of insecticides. Finally, we discuss how to develop "green" insecticides with a novel mode of action based on these high-resolution structures to overcome the resistance.