Molecular logic of pheromone recognition enables rational design of insect behavior modulators

Reproductive success across animal taxa relies on the unequivocal identification of volatile chemical cues used for sexual communication. These chemical signals, called pheromones, are often structurally nearly identical, sometimes differing only by the oxidation state of a functional group, yet elicit vastly different behaviors. The structural mechanisms driving this exquisite selectivity remain elusive, hindering the rational development of tools to modulate these pathways. Here, we decode the structural logic of pheromone recognition to rationally manipulate insect behavior. Using cryo-electron microscopy and functional mutagenesis, we show that the silkmoth Bombyx mori distinguishes between two highly similar compounds through the selective formation of a thio-hemiaminal, an uncommon covalent bond between the receptor and the pheromone. We leveraged these structural insights to undertake the first rational design of small molecules to disrupt insect mating. By engineering targeted electrophiles that irreversibly anchor to this reactive pocket, we successfully abolished long-range mate-tracking behavior in an agricultural pest model in vivo. This work identifies an unrecognized chemical strategy driving olfactory specificity and provides a blueprint for the rational design of airborne behavior modulators.