Anthelmintics are drugs used for controlling pathogenic helminths in animals and plants. The natural compound betaine and the recently developed synthetic compound monepantel are both anthelmintics that target the acetylcholine receptor ACR-23 and its homologs in nematodes. Here, we present cryo-electron microscopy structures of ACR-23 in apo, betaine-bound, and betaine- and monepantel-bound states. We show that ACR-23 forms a homo-pentameric channel, similar to some other pentameric ligand-gated ion channels (pLGICs). While betaine molecules are bound to the classical neurotransmitter sites in the inter-subunit interfaces in the extracellular domain, monepantel molecules are bound to allosteric sites formed in the inter-subunit interfaces in the transmembrane domain of the receptor. Although the pore remains closed in betaine-bound state, monepantel binding results in an open channel by wedging into the cleft between the transmembrane domains of two neighboring subunits, which causes dilation of the ion conduction pore. By combining structural analyses with site-directed mutagenesis, electrophysiology and in vivo locomotion assays, we provide insights into the mechanism of action of the anthelmintics monepantel and betaine.

中文翻译：

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驱虫药 monepantel 和甜菜碱对秀丽隐杆线虫乙酰胆碱受体 ACR-23 的分子效应的结构见解。


驱虫药是用于控制动植物病原蠕虫的药物。天然化合物甜菜碱和最近开发的合成化合物 monepantel 都是针对乙酰胆碱受体 ACR-23 及其在线虫中的同源物的驱虫药。在这里，我们展示了 ACR-23 在 apo、甜菜碱结合以及甜菜碱和莫奈帕特结合状态下的冷冻电子显微镜结构。我们发现 ACR-23 形成一个同型五聚体通道，类似于其他一些五聚体配体门控离子通道 （pLGIC）。甜菜碱分子与细胞外结构域亚基间界面中的经典神经递质位点结合，而 monepantel 分子与受体跨膜结构域中亚基间界面中形成的变构位点结合。尽管孔在甜菜碱结合状态下保持闭合，但 monepantel 结合通过楔入两个相邻亚基的跨膜结构域之间的裂缝产生开放通道，从而导致离子传导孔扩张。通过将结构分析与定点诱变、电生理学和体内运动测定相结合，我们提供了对驱虫药 monepantel 和甜菜碱的作用机制的见解。