Structural insights into the molecular effects of the anthelmintics monepantel and betaine on the Caenorhabditis elegans acetylcholine receptor ACR-23.

IF 9.4 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
EMBO Journal Pub Date : 2024-09-01 Epub Date: 2024-07-15 DOI:10.1038/s44318-024-00165-7
Fenglian Liu, Tianyu Li, Huihui Gong, Fei Tian, Yan Bai, Haowei Wang, Chonglin Yang, Yang Li, Fei Guo, Sheng Liu, Qingfeng Chen
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引用次数: 0

Abstract

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.

抗蠕虫药莫奈潘特尔和甜菜碱对优雅尾线虫乙酰胆碱受体 ACR-23 分子影响的结构性启示。
抗蠕虫药是用于控制动物和植物中致病蠕虫的药物。天然化合物甜菜碱和最近开发的合成化合物莫奈潘特尔都是针对线虫体内乙酰胆碱受体 ACR-23 及其同源物的抗蠕虫药。在这里,我们展示了ACR-23在apo、与甜菜碱结合以及与甜菜碱和莫奈潘特尔结合状态下的冷冻电镜结构。我们发现,ACR-23 形成了一个同源五聚体通道,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上的经典神经递质位点结合,而莫奈潘特尔分子则与受体跨膜结构域亚基间界面上形成的异构位点结合。虽然在甜菜碱结合状态下孔道仍处于关闭状态,但莫奈潘特尔结合后会楔入两个相邻亚基的跨膜结构域之间的裂隙,从而导致离子传导孔道扩张,从而形成开放通道。通过将结构分析与定点突变、电生理学和体内运动试验相结合,我们深入了解了杀虫药莫奈潘特尔和甜菜碱的作用机制。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
EMBO Journal
EMBO Journal 生物-生化与分子生物学
CiteScore
18.90
自引率
0.90%
发文量
246
审稿时长
1.5 months
期刊介绍: The EMBO Journal has stood as EMBO's flagship publication since its inception in 1982. Renowned for its international reputation in quality and originality, the journal spans all facets of molecular biology. It serves as a platform for papers elucidating original research of broad general interest in molecular and cell biology, with a distinct focus on molecular mechanisms and physiological relevance. With a commitment to promoting articles reporting novel findings of broad biological significance, The EMBO Journal stands as a key contributor to advancing the field of molecular biology.
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