期刊
NEURON
卷 109, 期 15, 页码 2443-+出版社
CELL PRESS
DOI: 10.1016/j.neuron.2021.05.031
关键词
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资金
- National Natural Science Foundation of China [31771115]
- National Key R&D Program of China [2017YFA0505700]
- Strategic Priority Research Program of Chinese Academy of Sciences [XDB32020000]
- Shanghai Municipal Science and Technology Major Project [2018SHZDZX05]
- Thousand Young Talents Program
- European Research Council (ERC grant) [693021]
- European Research Council (ERC) [693021] Funding Source: European Research Council (ERC)
NMDA receptors are important ion channels involved in synaptic transmission and plasticity. This study presents a series of cryo-EM structures of the human GluN1-GluN2A NMDA receptor, revealing the binding modes of different ligands or modulators and their effects on channel activation, inhibition, and allosteric transition.
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-doorblocker 9-aminoacridine within the LBDTMD linker region, differing from the conventional trappingblocker 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.
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