4.8 Article

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

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NATURE COMMUNICATIONS
卷 12, 期 1, 页码 -

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NATURE PORTFOLIO
DOI: 10.1038/s41467-021-27435-w

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  1. Projekt DEAL

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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.
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.

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