Structural basis for channel gating and blockade in tri-heteromeric GluN1-2B-2D NMDA receptor

Hyunook Kang; Max Epstein; Tue G Banke; Riley Perszyk; Noriko Simorowski; Srinu Paladugu; Dennis C Liotta; Stephen F Traynelis; Hiro Furukawa

doi:10.1016/j.neuron.2025.01.013

Structural basis for channel gating and blockade in tri-heteromeric GluN1-2B-2D NMDA receptor

Neuron. 2025 Feb 10:S0896-6273(25)00039-X. doi: 10.1016/j.neuron.2025.01.013. Online ahead of print.

Authors

Hyunook Kang¹, Max Epstein¹, Tue G Banke², Riley Perszyk², Noriko Simorowski¹, Srinu Paladugu³, Dennis C Liotta³, Stephen F Traynelis⁴, Hiro Furukawa⁵

Affiliations

¹ W.M. Keck Structural Biology Laboratory, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
² Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA, USA.
³ Department of Chemistry, Emory University, Atlanta, GA, USA.
⁴ Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA, USA; Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA, USA.
⁵ W.M. Keck Structural Biology Laboratory, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA. Electronic address: furukawa@cshl.edu.

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

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.

Keywords: MD simulations; channel blockade; channel gating; electrophysiology; ketamine binding site; single-particle cryo-EM; subtype-selective negative allosteric modulation; tri-heteromeric N-methyl-D-aspartate receptor.