19-May-2022

Tobias Raisch (Raunser group, Max Planck Institute of Molecular Physiology, Dortmund, Germany)

16.00 in HPM D7.2 and on Zoom: https://ethz.zoom.us/j/67396710587

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

Abstract:
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. In this project, we set out to understand how these compounds modulate ion translocation and whether there are insect-specific binding pockets. 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.