Small molecule modulation of the Drosophila Slo channel elucidated by cryo-EM

Slowpoke (Slo) potassium channels display extraordinarily high conductance, are synergistically activated by a positive transmembrane potential and high intracellular Ca2+ concentrations and are important targets for insecticides and antiparasitic drugs. However, it is unknown how these compounds modulate ion translocation and whether there are insect-specific binding pockets. Here, we report structures of Drosophila Slo in the Ca2+-bound and Ca2+-free form and in complex with the fungal neurotoxin verruculogen and the anthelmintic drug emodepside. Whereas the architecture and gating mechanism of Slo channels are conserved, potential insect-specific binding pockets exist. Verruculogen inhibits K+ transport by blocking the Ca2+-induced activation signal and precludes K+ from entering the selectivity filter. Emodepside decreases the conductance by suboptimal K+ coordination and uncouples ion gating from Ca2+ and voltage sensing. Our results expand the mechanistic understanding of Slo regulation and lay the foundation for the rational design of regulators of Slo and other voltage-gated ion channels. Slowpoke (Slo) channels are voltage-gated potassium channels that are activated by high intracellular Ca-2+ concentrations, and they are targets for insecticides and antiparasitic drugs. Here, the authors present the cryo-EM structures of the Drosophila melanogaster Slo channel in the Ca-2+-bound and Ca-2+-free conformations, as well as in complex with the fungal neurotoxin verruculogen and the anthelmintic drug emodepside and discuss the mechanisms by which they affect the activity of Slo.

Automated summary

Slowpoke (Slo) potassium channels, which have high conductance and are activated by positive transmembrane potential and high intracellular Ca2+ concentrations, are targets for insecticides and antiparasitic drugs. The study presents cryo-EM structures of Drosophila Slo in Ca2+-bound and Ca2+-free forms, as well as in complex with fungal neurotoxin verruculogen and anthelmintic drug emodepside, revealing potential insect-specific binding pockets and mechanisms of action on Slo channel activity.