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Publication Abstract from PubMed

Slowpoke (Slo) potassium channels display extraordinarily high conductance, are synergistically activated by a positive transmembrane potential and high intracellular Ca(2+) 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 Ca(2+)-bound and Ca(2+)-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 Ca(2+)-induced activation signal and precludes K(+) from entering the selectivity filter. Emodepside decreases the conductance by suboptimal K(+) coordination and uncouples ion gating from Ca(2+) 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.

Small molecule modulation of the Drosophila Slo channel elucidated by cryo-EM.,Raisch T, Brockmann A, Ebbinghaus-Kintscher U, Freigang J, Gutbrod O, Kubicek J, Maertens B, Hofnagel O, Raunser S Nat Commun. 2021 Dec 9;12(1):7164. doi: 10.1038/s41467-021-27435-w. PMID:34887422^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.