中科院脑智卓越创新中心学术交流暨生物物理与神经生物学前沿学术报告 CEBSIT Seminar and Frontiers in Biophysics and Neurobiology
报告题目: Structural Basis of the NMDA Receptor Gating and Allosteric Modulation 报告人: 竺淑佳 中科院神经科学研究所研究员 时间： 2017年11月17日（周五），下午：14:00-15:00 地点： 西区生物楼429会议室 主办单位：中科院脑科学与智能技术卓越创新中心 中国科学院脑功能与脑疾病重点实验室 中国科学技术大学生命科学学院 合肥微尺度物质科学国家实验室集成影像中心 报告简介： N-methyl-D-aspartate (NMDA) receptors are glutamate-gated, calcium-permeable ion channels that mediate synaptic transmission in the mammalian brain, have fundamental roles in brain development and function, and underpin learning and memory. NMDA receptor dysfunction is directly implicated in states of disease or injury ranging from seizure to ischemia and they are also targets of new rapid-acting therapeutic agents for the treatment of depression. Despite the fundamental importance of NMDA receptors in nervous system function and disease, there is little known about how the intact receptor transitions between inactive and active states, and how specific molecules antagonize or activate the receptor. Here we report single particle electron cryo-microscopy structures of the GluN1/GluN2B NMDA receptor in 3 novel conformations: an antagonist-bound state, an agonist-bound conformation, and a complex with agonists and the allosteric inhibitor, Ro25-6981. Together with double electron-electron resonance experiments, we show how competitive antagonists dramatically rupture the ligand-binding domain gating ‘ring’, how agonists promote reassembly of the ‘ring’ into a dimer-of-dimers configuration, and how allosteric inhibitors, acting within the amino terminal domain, further stabilize the ligand-binding domain layer. These structural and spectroscopic studies illuminate how the ligand-binding domain gating ‘ring’ is fundamental to signal transduction and gating in NMDA receptors.