Liu Sanling, Zheng Yining, Chen Haopeng, Li Xin, Yan Qipeng, Mu Wenjun, Fu Yaning, Chen Huan, Hou Hongwei, Liu Lei, Tian Changlin
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.
Beijing Life Science Academy, Beijing, China.
Cell Discov. 2025 Apr 8;11(1):35. doi: 10.1038/s41421-025-00788-y.
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.
α7烟碱型乙酰胆碱受体（nAChR）是一种五聚体配体门控离子通道，在认知、神经保护和抗炎中发挥重要作用。作为一个潜在的药物靶点，α7 nAChR对不同配体，特别是激动剂和正变构调节剂（PAM）具有不同的结合位点。激动剂-变构调节剂（Ago-PAM）既能直接激活α7 nAChR，又能对其进行变构调节。然而，Ago-PAM对α7 nAChR的调节机制尚未完全阐明。在此，我们分别展示了α7 nAChR与Ago-PAM GAT107和Ca结合处于开放和脱敏状态下的冷冻电镜结构。我们通过结构比较和功能测定得到的结果表明，GAT107对α7 nAChR的调节和钙增强作用存在变构机制，涉及胞外结构域-跨膜结构域（ECD-TMD）偶联区域的局部构象变化以及跨膜结构域的整体结构重排。这项工作提供了一种不同于传统激动剂结合的α7 nAChR门控新机制。这些发现将有助于药物设计，并丰富我们对五聚体配体门控离子通道的生物物理理解。
