Molecular insights into the α6β4 nicotinic acetylcholine receptor function and ligand recognition

Jiawei Su, Zhuoya Yu, Zhengji Yin, Zixuan Zhang, Jun Zhao, Yufei Meng, Renjie Li, Yiwei Gao, Hongwei Zhang, Rilei Yu () and Yan Zhao ()
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Jiawei Su: Chinese Academy of Sciences
Zhuoya Yu: Chinese Academy of Sciences
Zhengji Yin: Ocean University of China
Zixuan Zhang: Ocean University of China
Jun Zhao: Shandong Laboratory of Advanced Agricultural Sciences at Weifang
Yufei Meng: Chinese Academy of Sciences
Renjie Li: Chinese Academy of Sciences
Yiwei Gao: Chinese Academy of Sciences
Hongwei Zhang: Chinese Academy of Sciences
Rilei Yu: Ocean University of China
Yan Zhao: Chinese Academy of Sciences

Nature Communications, 2025, vol. 16, issue 1, 1-10

Abstract: Abstract The α6β4 nicotinic acetylcholine receptor (nAChR) is found in the sensory neurons of dorsal root ganglia. It is a promising therapeutic target for pain. However, the difficultly of heterologous functional expression of α6β4 receptor has hindered the discovery of drugs that target it. Here, we functionally express the human α6β4 receptor and determine the cryo-EM structures of α6β4 receptor in complex with its agonists, nicotine and the preclinical drug tebanicline. These structures were captured in non-conducting desensitized states. We elucidate that the stoichiometry of α- and β- subunits in the α6β4 receptor is 2α6:3β4. Furthermore, we identify the binding pockets for nicotine and tebanicline, demonstrating the essential residues contributing to ligand affinity and providing detailed molecular insights into why these agonists have different binding affinities despite both occupying the orthosteric site of the α6β4 receptor. These structures offer significant molecular insight into the function and ligand recognition of α6β4 receptor.

Date: 2025
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DOI: 10.1038/s41467-025-58333-0

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