9IIR

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

9IIR の概要

• エントリーDOI: 10.2210/pdb9iir/pdb
• EMDBエントリー: 60604
• 分子名称: 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)
• 機能のキーワード: ligand-gated ion channel, positive allosteric modulator, ago-pam, allosteric modulation, calcium potentiation, membrane protein
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 5
• 化学式量合計: 296575.54

構造登録者

Liu, S.,Zheng, Y.,Tian, C. (登録日: 2024-06-21, 公開日: 2025-04-23)

主引用文献

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

実験手法

ELECTRON MICROSCOPY (2.93 Å)