How a Scorpion Toxin Selectively Captures a Prey Sodium Channel: The Molecular and Evolutionary Basis Uncovered

The growing resistance of insects to chemical pesticides is reducing the effectiveness of conventional methods for pest control and thus, the development of novel insecticidal agents is imperative. Scorpion toxins specific for insect voltage-gated sodium channels (Navs) have been considered as one of the most promising insecticide alternatives due to their host specificity, rapidly evoked toxicity, biodegradability, and the lack of resistance. However, they have not been developed for uses in agriculture and public health, mainly because of a limited understanding of their molecular and evolutionary basis controlling their phylogenetic selectivity. Here, we show that the traditionally defined insect-selective scorpion toxin LqhIT2 specifically captures a prey Nav through a conserved trapping apparatus comprising a three-residue-formed cavity and a structurally adjacent leucine. The former serves as a detector to recognize and bind a highly exposed channel residue conserved in insects and spiders, two major prey items for scorpions; and the latter subsequently seizes the "moving" voltage sensor via hydrophobic interactions to reduce activation energy for channel opening, demonstrating its action in an enzyme-like manner. Based on the established toxin-channel interaction model in combination with toxicity assay, we enlarged the toxic spectrum of LqhIT2 to spiders and certain other arthropods. Furthermore, we found that genetic background-dependent cavity shapes determine the species selectivity of LqhIT2-related toxins. We expect that the discovery of the trapping apparatus will improve our understanding of the evolution and design principle of Nav-targeted toxins from a diversity of arthropod predators and accelerate their uses in pest control.