9IIR

human alpha 7 nicotinic acetylcholine receptor in complex with GAT107 and calcium (desensitized state)

Summary for 9IIR

• Entry DOI: 10.2210/pdb9iir/pdb
• EMDB information: 60604
• Descriptor: Neuronal acetylcholine receptor subunit alpha-7, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, (3aR,4S,9bS)-4-(4-bromophenyl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-sulfonamide, ... (6 entities in total)
• Functional Keywords: ligand-gated ion channel, positive allosteric modulator, ago-pam, allosteric modulation, calcium potentiation, membrane protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 5
• Total formula weight: 296575.54

Authors

Liu, S.,Zheng, Y.,Tian, C. (deposition date: 2024-06-21, release date: 2025-04-23)

Primary citation

Liu, S.,Zheng, Y.,Chen, H.,Li, X.,Yan, Q.,Mu, W.,Fu, Y.,Chen, H.,Hou, H.,Liu, L.,Tian, C.
Structural basis for allosteric agonism of human alpha 7 nicotinic acetylcholine receptors.
Cell Discov, 11:35-35, 2025

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 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.

PubMed: 40195322
DOI: 10.1038/s41421-025-00788-y

Experimental method

ELECTRON MICROSCOPY (2.93 Å)