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

• DOI: 10.1038/s41467-021-27435-w
• Publication Date: 2021-12-09T11:25:36Z
• Authors: Tobias Raisch; Andreas Brockmann; Ulrich Ebbinghaus...; Jörg Freigang; Oliver Gutbrod; Jan Kubicek; Barbara Maertens; Oliver Hofnagel; Stefan Raunser
• Keywords: Anthelmintics; 0301 basic medicine; Indoles; Calpain; Science; Q; Cryoelectron Microscopy; Biological Transport; Article; 03 medical and health sciences; Depsipeptides; Potassium; Animals; Drosophila Proteins; Calcium; Drosophila

AbstractSlowpoke (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.