EMD-31228
Structure of the human GluN1/GluN2A NMDA receptor in the glycine/glutamate/GNE-6901 bound state
EMD-31228
Single-particle4.0 Å
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Map released: 30/06/2021
Last modified: 23/10/2024
Sample Organism:
Homo sapiens
Sample: Structure of the human GluN1/GluN2A NMDA receptor in the glycine/glutamate/GNE-6901 bound state
Fitted models: 7eor (Avg. Q-score: 0.284)
Deposition Authors: Wang H
,
Zhu S
Sample: Structure of the human GluN1/GluN2A NMDA receptor in the glycine/glutamate/GNE-6901 bound state
Fitted models: 7eor (Avg. Q-score: 0.284)
Deposition Authors: Wang H
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Gating mechanism and a modulatory niche of human GluN1-GluN2A NMDA receptors.
Wang H
,
Lv S,
Stroebel D,
Zhang J,
Pan Y
,
Huang X,
Zhang X,
Paoletti P
,
Zhu S
(2021) Neuron , 109 , 2443 - 2456.e5
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(2021) Neuron , 109 , 2443 - 2456.e5
Abstract:
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 Å 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 LBD-TMD 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.
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 Å 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 LBD-TMD 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.