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-Structure paper
タイトル | Gating mechanism and a modulatory niche of human GluN1-GluN2A NMDA receptors. |
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ジャーナル・号・ページ | Neuron, Vol. 109, Issue 15, Page 2443-22456.e5, Year 2021 |
掲載日 | 2021年8月4日 |
著者 | Han Wang / Shiyun Lv / David Stroebel / Jinbao Zhang / Yijie Pan / Xuejing Huang / Xing Zhang / Pierre Paoletti / Shujia Zhu / |
PubMed 要旨 | 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 ...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. |
リンク | Neuron / PubMed:34186027 |
手法 | EM (単粒子) |
解像度 | 3.8 - 4.3 Å |
構造データ | EMDB-31227, PDB-7eoq: EMDB-31228, PDB-7eor: EMDB-31229, PDB-7eos: EMDB-31230, PDB-7eot: EMDB-31231, PDB-7eou: |
化合物 | ChemComp-NAG: ChemComp-7RC: ChemComp-6RM: ChemComp-J86: ChemComp-AA: |
由来 |
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キーワード | MEMBRANE PROTEIN / NMDA receptor |