2. Academic Validation
  3. Molecular insights into the α6β4 nicotinic acetylcholine receptor function and ligand recognition

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

  • Nat Commun. 2025 Apr 2;16(1):3153. doi: 10.1038/s41467-025-58333-0.
Jiawei Su # 1 2 3,  Zhuoya Yu # 1 2 3,  Zhengji Yin # 4 5,  Zixuan Zhang 4 5,  Jun Zhao 6,  Yufei Meng 1 2 3,  Renjie Li 1 2 3,  Yiwei Gao 1 2 3,  Hongwei Zhang 1,  Rilei Yu # 7 8,  Yan Zhao # 9 10
Affiliations

Affiliations

  • 1 National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.
  • 2 State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Beijing, 100101, China.
  • 3 College of Life Sciences, University of Chinese Academy of Sciences, Beijing, 100049, China.
  • 4 Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China.
  • 5 Laboratory for Marine Drugs and Bioproducts, Qingdao Marine Science and Technology Center, Qingdao, 266237, China.
  • 6 Peking University Institute of Advanced Agricultural Sciences, Shandong Laboratory of Advanced Agricultural Sciences at Weifang, Weifang, Shandong, 261000, China.
  • 7 Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China. ryu@ouc.edu.cn.
  • 8 Laboratory for Marine Drugs and Bioproducts, Qingdao Marine Science and Technology Center, Qingdao, 266237, China. ryu@ouc.edu.cn.
  • 9 National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China. zhaoy@ibp.ac.cn.
  • 10 State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Beijing, 100101, China. zhaoy@ibp.ac.cn.
  • # Contributed equally.
PMID: 40175361 DOI: 10.1038/s41467-025-58333-0
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.

Figures
Products