Kang, Hyunook, Epstein, Max, Banke, Tue G, Perszyk, Riley, Simorowski, Noriko, Paladugu, Srinu, Liotta, Dennis C, Traynelis, Stephen F, Furukawa, Hiro (February 2025) Structural basis for channel gating and blockade in tri-heteromeric GluN1-2B-2D NMDA receptor. Neuron. ISSN 0896-6273
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.
| Item Type: | Paper |
|---|---|
| Subjects: | Investigative techniques and equipment > microscopy > Cryo-electron microscopy Investigative techniques and equipment Investigative techniques and equipment > microscopy |
| CSHL Authors: | |
| Communities: | CSHL labs > Furukawa lab CSHL Cancer Center Shared Resources |
| SWORD Depositor: | CSHL Elements |
| Depositing User: | CSHL Elements |
| Date: | 10 February 2025 |
| Date Deposited: | 18 Feb 2025 13:57 |
| Last Modified: | 01 Jul 2025 15:24 |
| PMCID: | PMC11968220 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/41795 |
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