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

Tobias Raisch, Andreas Brockmann, Ulrich Ebbinghaus-Kintscher, Jörg Freigang, Oliver Gutbrod, Jan Kubicek, Barbara Maertens, Oliver Hofnagel, Stefan Raunser

Nature communications 2021 Dec 09

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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. © 2021. The Author(s).

Citation

Tobias Raisch, Andreas Brockmann, Ulrich Ebbinghaus-Kintscher, Jörg Freigang, Oliver Gutbrod, Jan Kubicek, Barbara Maertens, Oliver Hofnagel, Stefan Raunser. Small molecule modulation of the Drosophila Slo channel elucidated by cryo-EM. Nature communications. 2021 Dec 09;12(1):7164