9D3C

Gly-,Glu-,(S)-(+)-ketamine bound GluN1a-2B-2D NMDAR

9D3C の概要

• エントリーDOI: 10.2210/pdb9d3c/pdb
• EMDBエントリー: 46531
• 分子名称: Glutamate receptor ionotropic, NMDA 1, Glutamate receptor ionotropic, NMDA 2B, Glutamate receptor ionotropic, NMDA 2D, ... (8 entities in total)
• 機能のキーワード: n-methyl-d-aspartate receptor, (s)-(+)-ketamine, glun2b, glun2d, membrane protein
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 381002.62

構造登録者

Hyunook, K.,Hiro, F. (登録日: 2024-08-09, 公開日: 2025-02-26, 最終更新日: 2025-04-16)

主引用文献

Kang, H.,Epstein, M.,Banke, T.G.,Perszyk, R.,Simorowski, N.,Paladugu, S.,Liotta, D.C.,Traynelis, S.F.,Furukawa, H.
Structural basis for channel gating and blockade in tri-heteromeric GluN1-2B-2D NMDA receptor.
Neuron, 113:991-, 2025

PubMed Abstract: Discrete activation of N-methyl-D-aspartate receptor (NMDAR) subtypes by glutamate and the co-agonist glycine is fundamental to neuroplasticity. A distinct variant, the tri-heteromeric receptor, comprising glycine-binding GluN1 and two types of glutamate-binding GluN2 subunits, exhibits unique pharmacological characteristics, notably enhanced sensitivity to the anti-depressant channel blocker S-(+)-ketamine. Despite its significance, the structural mechanisms underlying ligand gating and channel blockade of tri-heteromeric NMDARs remain poorly understood. Here, we identify and characterize tri-heteromeric GluN1-2B-2D NMDAR in the adult brain, resolving its structures in the activated, inhibited, and S-(+)-ketamine-blocked states. These structures reveal the ligand-dependent conformational dynamics that modulate the tension between the extracellular domain and transmembrane channels, governing channel gating and blockade. Additionally, we demonstrate that the inhibitor (S)-DQP-997-74 selectively decouples linker tension in GluN2D, offering insights into subtype-selective targeting for cognitive modulation.

PubMed: 39954679
DOI: 10.1016/j.neuron.2025.01.013

実験手法

ELECTRON MICROSCOPY (3.96 Å)