The unconventional activation of the muscarinic acetylcholine receptor M4R by diverse ligands

doi:10.1038/s41467-022-30595-y

	The unconventional activation of the muscarinic acetylcholine receptor M4R by diverse ligands
	Wang, Jingjing1 ; Wu, Meng1 ; Chen, Zhangcheng 2; Wu, Lijie1 ; Wang, Tian1,3 ; Cao, Dongmei 2; Wang, Huan1 ; Liu, Shenhui1,3 ; Xu, Yueming1 ; Li, Fei1 ; Liu, Junlin1 ; Chen, Na1 ; Zhao, Suwen1,3 ; Cheng, Jianjun1 ; Wang, Sheng 2; Hua, Tian1,3
	2022-05-23
发表期刊	NATURE COMMUNICATIONS
EISSN	2041-1723
卷号	13 期号:1
发表状态	已发表
DOI	10.1038/s41467-022-30595-y
摘要	Muscarinic acetylcholine receptors (mAChRs) respond to the neurotransmitter acetylcholine and play important roles in human nervous system. Muscarinic receptor 4 (M4R) is a promising drug target for treating neurological and mental disorders, such as Alzheimer’s disease and schizophrenia. However, the lack of understanding on M4R’s activation by subtype selective agonists hinders its therapeutic applications. Here, we report the structural characterization of M4R selective allosteric agonist, compound-110, as well as agonist iperoxo and positive allosteric modulator LY2119620. Our cryo-electron microscopy structures of compound-110, iperoxo or iperoxo-LY2119620 bound M4R-G complex reveal their different interaction modes and activation mechanisms of M4R, and the M4R-ip-LY-G structure validates the cooperativity between iperoxo and LY2119620 on M4R. Through the comparative structural and pharmacological analysis, compound-110 mostly occupies the allosteric binding pocket with vertical binding pose. Such a binding and activation mode facilitates its allostersic selectivity and agonist profile. In addition, in our schizophrenia-mimic mouse model study, compound-110 shows antipsychotic activity with low extrapyramidal side effects. Thus, this study provides structural insights to develop next-generation antipsychotic drugs selectively targeting on mAChRs subtypes.
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收录类别	SCIE
语种	英语
Scopus 记录号	2-s2.0-85130430711
来源库	Scopus
引用统计
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/216465
专题	生命科学与技术学院_硕士生 iHuman研究所_公共科研平台_IT平台 iHuman研究所_公共科研平台_昆虫细胞培养平台 iHuman研究所_PI研究组_赵素文组 iHuman研究所_PI研究组_程建军组 iHuman研究所_科学装置(X)_膜蛋白同步辐射线站生命科学与技术学院_博士生 iHuman研究所_PI研究组_华甜组
通讯作者	Cheng, Jianjun; Wang, Sheng; Hua, Tian
作者单位	1.iHuman Institute,ShanghaiTech University,Shanghai,201210,China 2.State Key Laboratory of Molecular Biology,Shanghai Institute of Biochemistry and Cell Biology,Center for Excellence in Molecular Cell Science,Chinese Academy of Sciences,Shanghai,200031,China 3.School of Life Science and Technology,ShanghaiTech University,Shanghai,201210,China
第一作者单位	iHuman研究所
通讯作者单位	iHuman研究所; 生命科学与技术学院
第一作者的第一单位	iHuman研究所
推荐引用方式 GB/T 7714	Wang, Jingjing,Wu, Meng,Chen, Zhangcheng,et al. The unconventional activation of the muscarinic acetylcholine receptor M4R by diverse ligands[J]. NATURE COMMUNICATIONS,2022,13(1).
APA	Wang, Jingjing.,Wu, Meng.,Chen, Zhangcheng.,Wu, Lijie.,Wang, Tian.,...&Hua, Tian.(2022).The unconventional activation of the muscarinic acetylcholine receptor M4R by diverse ligands.NATURE COMMUNICATIONS,13(1).
MLA	Wang, Jingjing,et al."The unconventional activation of the muscarinic acetylcholine receptor M4R by diverse ligands".NATURE COMMUNICATIONS 13.1(2022).