9UN2

native NMDAR receptor-GluN1/N2B in the inactive state

Summary for 9UN2

• Entry DOI: 10.2210/pdb9un2/pdb
• EMDB information: 64337
• Descriptor: Glutamate receptor ionotropic, NMDA 1, Glutamate receptor ionotropic, NMDA 2B, 2-acetamido-2-deoxy-beta-D-glucopyranose (3 entities in total)
• Functional Keywords: native, nmda receptor, ionotropic ion channel, excitatory neurotransmitter, membrane protein
• Biological source: Mus musculus (house mouse); More
• Total number of polymer chains: 4
• Total formula weight: 369640.49

Authors

Yu, J.,Xu, R.S.,Ge, J.P. (deposition date: 2025-04-23, release date: 2026-02-18, Last modification date: 2026-02-25)

Primary citation

Xu, R.,Jiang, Q.,Xu, H.,Zhang, L.,Hu, X.,Lu, Z.,Deng, H.,Xiong, H.,Zhang, S.,Chen, Z.,Ge, Y.,Zhu, Z.,Zhang, Y.,Chen, Y.,Ge, J.,Yu, J.
Conformational diversity and fully opening mechanism of native NMDA receptor.
Nature, 2026

PubMed Abstract: N-methyl-D-aspartate receptors (NMDARs) are glutamate-gated ion channels that mediate excitatory neurotransmission throughout the brain. As obligate heterotetramers, their activation requires the binding of both glycine and glutamate. Although recent structural studies have provided insights into endogenous receptors from select brain regions, most previous work has relied on recombinant receptors and engineered constructs, which limits our understanding of native NMDARs across the whole brain. Here we identify and resolve ten distinct native NMDAR assemblies from the whole-brain tissue of female C57BL/6 mice using immunoaffinity purification, single-molecule total internal reflection fluorescence microscopy and cryo-electron microscopy. Analyses of the GluN1-GluN2A(S1), GluN1-GluN2A(S2), GluN1-GluN2A(S3), GluN1-GluN2B, GluN1-GluN2A-GluN2B(S1), GluN1-GluN2A-GluN2B(S2), GluN1-GluN2A-GluNX(S1), GluN1-GluN2A-GluNX(S2), GluN1-GluN2B-GluNX and GluN1-GluNX structures reveal that GluN2A is the most prevalent subunit across assemblies. Moreover, the substantial conformational flexibility observed in the GluN2A amino-terminal domain may explain its fast kinetics and dominant role in gating. Dynamic movements of S-ketamine were also captured at the channel vestibule, as was pore dilation in both the GluN1 and GluN2B subunits of a native GluN1-GluN2B receptor. The latter observation represents a previously unknown fully open state of NMDAR. Our large collection of heterogeneous NMDAR structures from whole brain reveals previously unrecognized properties of conformational diversity and channel dilation.

PubMed: 41673155
DOI: 10.1038/s41586-026-10139-w

Experimental method

ELECTRON MICROSCOPY (4.3 Å)