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 and Stefan Raunser ()
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Tobias Raisch: Max Planck Institute of Molecular Physiology
Andreas Brockmann: Bayer AG, Crop Science Division
Ulrich Ebbinghaus-Kintscher: Bayer AG, Crop Science Division
Jörg Freigang: Bayer AG, Crop Science Division
Oliver Gutbrod: Bayer AG, Crop Science Division
Jan Kubicek: Cube Biotech GmbH
Barbara Maertens: Cube Biotech GmbH
Oliver Hofnagel: Max Planck Institute of Molecular Physiology
Stefan Raunser: Max Planck Institute of Molecular Physiology

Nature Communications, 2021, vol. 12, issue 1, 1-12

Abstract: 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. 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.

Date: 2021
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DOI: 10.1038/s41467-021-27435-w

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