Zarkadas Eleftherios, Pebay-Peyroula Eva, Thompson Mackenzie John, Schoehn Guy, Uchański Tomasz, Steyaert Jan, Chipot Christophe, Dehez Francois, Baenziger John Edward, Nury Hugues
Université Grenoble Alpes, CNRS, CEA, IBS, F-38000 Grenoble, France.
Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada.
Neuron. 2022 Apr 20;110(8):1358-1370.e5. doi: 10.1016/j.neuron.2022.01.013. Epub 2022 Feb 8.
Fast synaptic communication requires receptors that respond to the presence of neurotransmitter by opening an ion channel across the post-synaptic membrane. The muscle-type nicotinic acetylcholine receptor from the electric fish, Torpedo, is the prototypic ligand-gated ion channel, yet the structural changes underlying channel activation remain undefined. Here we use cryo-EM to solve apo and agonist-bound structures of the Torpedo nicotinic receptor embedded in a lipid nanodisc. Using both a direct biochemical assay to define the conformational landscape and molecular dynamics simulations to assay flux through the pore, we correlate structures with functional states and elucidate the motions that lead to pore activation of a heteromeric nicotinic receptor. We highlight an underappreciated role for the complementary subunit in channel gating, establish the structural basis for the differential agonist affinities of α/δ versus α /γ sites, and explain why nicotine is less potent at muscle nicotinic receptors compared to neuronal ones.
快速突触通讯需要通过打开突触后膜上的离子通道来响应神经递质存在的受体。电鱼电鳐的肌肉型烟碱型乙酰胆碱受体是典型的配体门控离子通道，但通道激活背后的结构变化仍不明确。在这里，我们使用冷冻电镜来解析嵌入脂质纳米盘的电鳐烟碱受体的无配体和激动剂结合结构。我们使用直接生化分析来定义构象景观，并通过分子动力学模拟来分析通过孔道的通量，将结构与功能状态相关联，并阐明导致异源烟碱受体孔道激活的运动。我们强调了互补亚基在通道门控中未被充分认识的作用，建立了α/δ与α/γ位点不同激动剂亲和力的结构基础，并解释了为什么与神经元烟碱受体相比，尼古丁对肌肉烟碱受体的效力较低。
