Department of Structural Biochemistry, Max Planck Institute of Molecular Physiology, 44227, Dortmund, Germany.
Bayer AG, Crop Science Division, D-40789, Monheim am Rhein, Germany.
Nat Commun. 2021 Dec 9;12(1):7164. doi: 10.1038/s41467-021-27435-w.
Slowpoke (Slo) potassium channels display extraordinarily high conductance, are synergistically activated by a positive transmembrane potential and high intracellular Ca 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-bound and Ca-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-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 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）钾通道具有极高的电导，可协同由正跨膜电位和高细胞内 Ca 浓度激活，是杀虫剂和抗寄生虫药物的重要靶点。然而，这些化合物如何调节离子转运以及是否存在昆虫特异性结合口袋尚不清楚。在这里，我们报告了果蝇 Slo 在 Ca 结合和无 Ca 形式以及与真菌神经毒素 verruculogen 和驱虫药 emodepside 复合物的结构。尽管 Slo 通道的结构和门控机制是保守的，但存在潜在的昆虫特异性结合口袋。Verruculogen 通过阻断 Ca 诱导的激活信号来抑制 K 转运，并阻止 K 进入选择性过滤器。Emodepside 通过次优的 K 协调降低电导，并使离子门控与 Ca 和电压感应解耦。我们的研究结果扩展了 Slo 调节的机制理解，并为 Slo 和其他电压门控离子通道调节剂的合理设计奠定了基础。
