Molecular insights into the α6β4 nicotinic acetylcholine receptor function and ligand recognition
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.
Authors
- Zhuoya Yu (ORCID: https://orcid.org/0000-0002-0370-2871)
- Hongwei Zhang (ORCID: https://orcid.org/0000-0003-1514-3103)
- Yiwei Gao (ORCID: https://orcid.org/0000-0001-8169-9332)
- Zhengji Yin
- Yan Zhao (ORCID: https://orcid.org/0000-0002-4348-256X)
- Jiawei Su (ORCID: https://orcid.org/0000-0002-6124-5007)
- Rilei Yu (ORCID: https://orcid.org/0000-0001-6625-2014)
- Zixuan Zhang (ORCID: https://orcid.org/0009-0008-8958-4917)
- Jun Zhao (ORCID: https://orcid.org/0009-0006-6190-0469)
- Renjie Li (ORCID: https://orcid.org/0000-0003-1714-9939)
- Yufei Meng (ORCID: https://orcid.org/0000-0001-7835-4237)
Institutions
- Chinese Academy of Sciences (CN)
- Institute of Biophysics (CN)
- Qingdao National Laboratory for Marine Science and Technology (CN)
- University of Chinese Academy of Sciences (CN)
- Ocean University of China (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-04-02
- DOI
- https://doi.org/10.1038/s41467-025-58333-0
- Citations
- 5
- Primary Topic
- Nicotinic Acetylcholine Receptors Study
- Type
- article
- Field-Weighted Citation Impact
- 4.03
Funders
- National Natural Science Foundation of China
- Chinese Academy of Sciences
- National Key Research and Development Program of China
- Institute of Biophysics, Chinese Academy of Sciences
- National Laboratory of Biomacromolecules