Download MendeleyStructural basis for allosteric agonism of human alpha 7 nicotinic acetylcholine receptors.
Liu, S., Zheng, Y., Chen, H., Li, X., Yan, Q., Mu, W., Fu, Y., Chen, H., Hou, H., Liu, L., Tian, C.(2025) Cell Discov 11: 35-35
- PubMed: 40195322
- DOI: https://doi.org/10.1038/s41421-025-00788-y
- Primary Citation of Related Structures:
9IIR, 9IIV - PubMed Abstract:
The α7 nicotinic acetylcholine receptor (nAChR), a pentameric ligand-gated ion channel, plays important roles in cognition, neuroprotection, and anti-inflammation. As a potential drug target, α7 nAChR has different binding sites for different ligands, particularly agonists and positive allosteric modulators (PAMs). Ago-PAMs can both directly activate and allosterically modulate α7 nAChR. However, the mechanism underlying α7 nAChR modulation by ago-PAM has yet to be fully elucidated. Here, we present cryo-EM structures of α7 nAChR in complex with the ago-PAM GAT107 and Ca 2+ in the open and desensitized states, respectively. Our results from both structural comparisons and functional assays suggest an allosteric mechanism underlying GAT107 modulation and calcium potentiation of α7 nAChR, involving local conformational changes in the ECD-TMD coupling region and a global structural rearrangement in the transmembrane domain. This work provides a new mechanism of α7 nAChR gating distinct from that of conventional agonist binding. These findings would aid in drug design and enrich our biophysical understanding of pentameric ligand-gated ion channels.
Organizational Affiliation:
Division of Life Sciences and Medicine, Joint Center for Biological Analytical Chemistry, Anhui Engineering Laboratory of Peptide Drug, University of Science and Technology of China, Hefei, Anhui, China. [email protected].
