Structural basis for allosteric agonism of human α7 nicotinic acetylcholine receptors

作者：Sanling Liu, Yining Zheng, Haopeng Chen, Xin Li, Qipeng Yan, Wenjun Mu, Yaning Fu, Huan Chen, Hongwei Hou, Lei Liu, Changlin Tian · 发表于：Cell Discovery · 年份：2025 · DOI：10.1038/s41421-025-00788-y · 被引用次数：12 · 研究领域：Nicotinic Acetylcholine Receptors Study、Receptor Mechanisms and Signaling、Photoreceptor and optogenetics research

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.