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

文献类型：期刊论文

作者Liu, Fenglian7; Li, Tianyu5,6; Gong, Huihui7; Tian, Fei7; Bai, Yan7; Wang, Haowei7; Yang, Chonglin7; Li, Yang3,4,5; Guo, Fei3,4,5; Liu, Sheng1,2
刊名EMBO JOURNAL
出版日期2024-07-15
页码20
关键词Acetylcholine Receptor Monepantel Betaine Anthelmintics Cryo-EM Structure
ISSN号0261-4189
DOI10.1038/s44318-024-00165-7
通讯作者Guo, Fei(guofei@simm.ac.cn) ; Liu, Sheng(sliu520@mail.ustc.edu.cn) ; Chen, Qingfeng(qingfengchen@ynu.edu.cn)
英文摘要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.
WOS关键词X-RAY-STRUCTURE ; GATING MECHANISM ; ION-CHANNEL ; VALIDATION ; DISCOVERY ; PROGRAM ; SYSTEM
资助项目the National Natural Science Foundation of China[2020YFA0908503] ; Ministry of Science and Technology of China[32071202] ; Ministry of Science and Technology of China[32271012] ; Ministry of Science and Technology of China[32100129] ; Ministry of Science and Technology of China[31371066] ; Ministry of Science and Technology of China[32371005] ; National Natural Science Foundation of China[20JCJQJC00080] ; Tianjin Fund for Distinguished Young Scholars[202401AV070004] ; Yunnan Fund for Distinguished Young Scholars[184319071000] ; Yunnan Fund for Distinguished Young Scholars[19140903102] ; Shanghai Municipal Science and Technology Major Project[KC-23236410] ; Postgraduate Research and Innovation Foundation of Yunnan University
WOS研究方向Biochemistry & Molecular Biology ; Cell Biology
语种英语
WOS记录号WOS:001272530800002
出版者SPRINGERNATURE
源URL[http://119.78.100.183/handle/2S10ELR8/312404]  
专题新药研究国家重点实验室
通讯作者Guo, Fei; Liu, Sheng; Chen, Qingfeng
作者单位1.Shenzhen Childrens Hosp, Dept Infect Dis, Shenzhen 518038, Guangdong, Peoples R China
2.Shenzhen Childrens Hosp, Inst Pediat, Shenzhen 518026, Guangdong, Peoples R China
3.Fudan Univ, Huashan Hosp, Natl Clin Res Ctr Aging & Med, Shanghai 200040, Peoples R China
4.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
5.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
6.Tongji Univ, Shanghai Matern & Infant Hosp 1, Shanghai Inst Maternal Fetal Med & Gynecol Oncol, Sch Med,Dept Anesthesiol,Shanghai Key Lab Maternal, Shanghai 201204, Peoples R China
7.Yunnan Univ, Ctr Life Sci, Yunnan Key Lab Cell Metab & Dis, Sch Life Sci,State Key Lab Conservat & Utilizat Bi, Kunming 650091, Peoples R China
推荐引用方式
GB/T 7714		 Liu, Fenglian,Li, Tianyu,Gong, Huihui,et al. Structural insights into the molecular effects of the anthelmintics monepantel and betaine on the Caenorhabditis elegans acetylcholine receptor ACR-23[J]. EMBO JOURNAL,2024:20.
APA Liu, Fenglian.,Li, Tianyu.,Gong, Huihui.,Tian, Fei.,Bai, Yan.,...&Chen, Qingfeng.(2024).Structural insights into the molecular effects of the anthelmintics monepantel and betaine on the Caenorhabditis elegans acetylcholine receptor ACR-23.EMBO JOURNAL,20.
MLA Liu, Fenglian,et al."Structural insights into the molecular effects of the anthelmintics monepantel and betaine on the Caenorhabditis elegans acetylcholine receptor ACR-23".EMBO JOURNAL (2024):20.

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来源：上海药物研究所

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