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Neuron, Feb 10 2025, S0896-6273(25)00039-X | https://doi.org/10.1016/j.neuron.2025.01.013
Structural basis for channel gating and blockade in tri-heteromeric GluN1-2B-2D NMDA receptor
Hyunook Kang 1, Max Epstein 1, Tue G. Banke 2, Riley Perszyk 2, Noriko Simorowski 1, Srinu Paladugu 3, Dennis C. Liotta 3, Stephen F. Traynelis 2 4, Hiro Furukawa 1 5 *
1W.M. Keck Structural Biology Laboratory, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA
2Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA, USA
3Department of Chemistry, Emory University, Atlanta, GA, USA
4Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA, USA
5Lead contact
2Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA, USA
3Department of Chemistry, Emory University, Atlanta, GA, USA
4Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA, USA
5Lead contact
*Corresponding author: correspondence to Hiro Furukawa
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.
논문정보
- Research article
- 2025년 02월 (BRIC 등록일 2025-02-19)
- 국외 연구진
- 생명과학 > 구조생물 및 생물물리학
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