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| Title | Conformational diversity and fully opening mechanism of native NMDA receptor. |
|---|---|
| Journal, issue, pages | Nature, Year 2026 |
| Publish date | Feb 11, 2026 |
 Authors | Ruisheng Xu / Qiqi Jiang / Hongwei Xu / Lu Zhang / Xiangzi Hu / Zizhuo Lu / Huaqin Deng / Haolin Xiong / Sensen Zhang / Zhongwen Chen / Yifan Ge / Zhengjiang Zhu / Yaoyang Zhang / Yelin Chen / Jingpeng Ge / Jie Yu /  |
| 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 ...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. |
 External links | Nature / PubMed:41673155 |
| Methods | EM (single particle) |
| Resolution | 2.98 - 6.37 Å |
| Structure data |  EMDB-64277: native GluN1/N2B receptor in the fully open state  EMDB-64278: native GluN1/N2B receptor in the open state TMD focused map  EMDB-64279: native GluN1/N2A/N2B-s1 consensus map in the closed state  EMDB-64280: native GluN1/N2A/N2B-s1-TMD focused map in the closed state  EMDB-64281: native GluN1/N2A/N2B-subtype2 consensus map in the closed state  EMDB-64283: native GluN1/N2A/N2B-S2-TMD focused map in the closed state  EMDB-64284: native GluN1/N2A-subtype 1-TMD focused  EMDB-64285: native GluN1/N2B-subtype1 in closed state  EMDB-64289: native GluN1/N2A-subtype2-consensus map  EMDB-64290: native GluN1/N2A-subtype2-TMD focused map  EMDB-64292: native GluN1/N2A-S3-consensus map in the closed state  EMDB-64294: native GluN1/N2A-S3 TMD focused map in the closed state  EMDB-64295: native GluN1/N2B receptor consensus map in the closed state  EMDB-64296: native GluN1/N2B-TMD-focused map in the closed state  EMDB-64297: native GluN1/N2B/NX-consensus map in the closed state  EMDB-64298: native GluN1/N2A/NX-TMD-focused map in the closed state  EMDB-64299: native GluN1/N2B/NX composite map in the closed state  EMDB-64300: native GluN1_N2A_NX_subtype-consensus map in the closed state  EMDB-64301: native GluN1_N2A_NX_subtype1_TMD_focused map in the closed state  EMDB-64302: native GluN1_N2A_NX_subtype1_composite_map in the closed state  EMDB-64303: native GluN1_N2A_NX_S2_consensus map  EMDB-64304: native GluN1_N2A_NX_subtype2_TMD_focused  EMDB-64305: native GluN1_N2A_NX_subtype2_composite map  EMDB-64306: native GluN1_NX_consensus_map  EMDB-64307: native GluN1_NX TMD focused map  EMDB-64308: native GluN1_GluNX composite map  EMDB-64309: native native NMDA receptor-GluN1/N2B in inactive state TMD focused map  EMDB-64310: native NMDA receptor-GluN1/N2B in the inactive state consensus map  EMDB-64311: native NMDA receptor-GluN1/N2A in inactive state consensus map  EMDB-64313: native NMDA receptor-GluN1/N2A/N2B in inactive state consensus map  EMDB-64314: native NMDA receptor-GluN1/N2A/N2B in inactive state TMD focused map  EMDB-64315: native NMDA receptor-GluN1/N2B/NX in the open state consensus map  EMDB-64316: native NMDA receptor-GluN1/N2B/NX in the open state TMD focused map  EMDB-64317: native NMDA receptor-GluN1/N2B/NX in the open state  EMDB-64318: native NMDA receptor-GluN1/N2A in inactive state TMD focused map  EMDB-64319: native NMDA receptor-GluN1/N2B/NX in inactive state consensus map  EMDB-64320: native NMDA receptor-GluN1/N2B/NX in inactive state TMD focused map  EMDB-64321: native NMDA receptor-GluN1/N2B/NX in inactive state  EMDB-64326: native NMDA receptor-GluN1-N2A-NX consensus map  EMDB-64327: native NMDA receptor-GlUN1/N2A/NX TMD focused map  EMDB-64328: native NMDA receptor-GluN1/N2A/NX composite map  EMDB-64330: native NMDA receptor-GluN1/NX consensus map  EMDB-64331: native NMDA receptor-GluN1/NX TMD focused map  EMDB-64332: native NMDA receptor-GluN1/NX composite map EMDB-64337, PDB-9un2: EMDB-64338, PDB-9un3: EMDB-64353, PDB-9unj: EMDB-64354, PDB-9unk: EMDB-64356, PDB-9unm: EMDB-64357, PDB-9unn: EMDB-64358, PDB-9uno: EMDB-64359, PDB-9unp: EMDB-64360, PDB-9unq: EMDB-64361, PDB-9unr: |
| Chemicals |  ChemComp-NAG:  ChemComp-GLY:  ChemComp-GLU:  ChemComp-JC9: |
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 Keywords | MEMBRANE PROTEIN / native / NMDA receptor / ionotropic ion channel / excitatory neurotransmitter / MEMBRANE / open state / inotropic ion channel / MEMBRANE PROTEIN/IMMUNE SYSTEM / ion channel / MEMBRANE PROTEIN-IMMUNE SYSTEM complex |
mus musculus (house mouse)
Homo sapiens (human)