Gating mechanism and a modulatory niche of human GluN1-GluN2A NMDA receptors

被引:43
作者
Wang, Han [1 ,2 ]
Lv, Shiyun [1 ,2 ]
Stroebel, David [3 ]
Zhang, Jinbao [1 ]
Pan, Yijie [1 ]
Huang, Xuejing [1 ]
Zhang, Xing [4 ,5 ]
Paoletti, Pierre [3 ]
Zhu, Shujia [1 ,2 ,6 ]
机构
[1] Chinese Acad Sci, Inst Neurosci, CAS Ctr Excellence Brain Sci & Intelligence Tech, State Key Lab Neurosci, Shanghai 200031, Peoples R China
[2] Univ Chinese Acad Sci, Beijing 100049, Peoples R China
[3] Univ PSL, CNRS, Inst Biol Ecole Normale Super, Ecole Normale Super,INSERM, Paris, France
[4] Zhejiang Univ, Dept Biophys, Ctr Cryo Electron Microscopy, Sch Med,Sir Run Run Shaw Hosp, Hangzhou, Peoples R China
[5] Zhejiang Univ, Dept Pathol, Ctr Cryo Electron Microscopy, Sch Med,Sir Run Run Shaw Hosp, Hangzhou, Peoples R China
[6] Shanghai Ctr Brain Sci & Brain Inspired Intellige, Shanghai 201210, Peoples R China
基金
欧洲研究理事会; 中国国家自然科学基金; 国家重点研发计划;
关键词
POSITIVE ALLOSTERIC MODULATORS; LIGAND-BINDING DOMAIN; D-ASPARTATE RECEPTORS; STRUCTURAL BASIS; GLUN2A-CONTAINING NMDARS; EXTRACELLULAR VESTIBULE; SYNAPTIC PLASTICITY; PROTON INHIBITION; IN-VIVO; EXPRESSION;
D O I
10.1016/j.neuron.2021.05.031
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
N-methyl-D-aspartate (NMDA) receptors are glutamate-gated calcium-permeable ion channels that are widely implicated in synaptic transmission and plasticity. Here, we report a gallery of cryo-electron microscopy (cryo-EM) structures of the human GluN1-GluN2A NMDA receptor at an overall resolution of 4 A in complex with distinct ligands or modulators. In the full-length context of GluN1-GluN2A receptors, we visualize the competitive antagonists bound to the ligand-binding domains (LBDs) of GluN1 and GluN2A subunits, respectively. We reveal that the binding of positive allosteric modulator shortens the distance between LBDs and the transmembrane domain (TMD), which further stretches the opening of the gate. In addition, we unexpectedly visualize the binding cavity of the "foot-in-the-door"blocker 9-aminoacridine within the LBDTMD linker region, differing from the conventional "trapping"blocker binding site at the vestibule within the TMD. Our study provides molecular insights into the crosstalk between LBDs and TMD during channel activation, inhibition, and allosteric transition.
引用
收藏
页码:2443 / +
页数:20
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