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

Jingjing Wang, Meng Wu, Zhangcheng Chen, Lijie Wu, Tian Wang, Dongmei Cao, Huan Wang, Shenhui Liu, Yueming Xu, Fei Li, Junlin Liu, Na Chen, Suwen Zhao, Jianjun Cheng (), Sheng Wang () and Tian Hua ()
Additional contact information
Jingjing Wang: ShanghaiTech University
Meng Wu: ShanghaiTech University
Zhangcheng Chen: Chinese Academy of Sciences
Lijie Wu: ShanghaiTech University
Tian Wang: ShanghaiTech University
Dongmei Cao: Chinese Academy of Sciences
Huan Wang: ShanghaiTech University
Shenhui Liu: ShanghaiTech University
Yueming Xu: ShanghaiTech University
Fei Li: ShanghaiTech University
Junlin Liu: ShanghaiTech University
Na Chen: ShanghaiTech University
Suwen Zhao: ShanghaiTech University
Jianjun Cheng: ShanghaiTech University
Sheng Wang: Chinese Academy of Sciences
Tian Hua: ShanghaiTech University

Nature Communications, 2022, vol. 13, issue 1, 1-10

Abstract: Abstract 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-Gi complex reveal their different interaction modes and activation mechanisms of M4R, and the M4R-ip-LY-Gi 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.

Date: 2022
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DOI: 10.1038/s41467-022-30595-y

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