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Structure paper

タイトルConformational diversity and fully opening mechanism of native NMDA receptor.
ジャーナル・号・ページNature, Year 2026
掲載日2026年2月11日
著者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 要旨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.
リンクNature / PubMed:41673155
手法EM (単粒子)
解像度2.98 - 6.37 Å
構造データ

EMDB-64277: native GluN1/N2B receptor in the fully open state
手法: EM (単粒子) / 解像度: 3.37 Å

EMDB-64278: native GluN1/N2B receptor in the open state TMD focused map
手法: EM (単粒子) / 解像度: 3.9 Å

EMDB-64279: native GluN1/N2A/N2B-s1 consensus map in the closed state
手法: EM (単粒子) / 解像度: 2.98 Å

EMDB-64280: native GluN1/N2A/N2B-s1-TMD focused map in the closed state
手法: EM (単粒子) / 解像度: 3.37 Å

EMDB-64281: native GluN1/N2A/N2B-subtype2 consensus map in the closed state
手法: EM (単粒子) / 解像度: 3.27 Å

EMDB-64283: native GluN1/N2A/N2B-S2-TMD focused map in the closed state
手法: EM (単粒子) / 解像度: 3.39 Å

EMDB-64284: native GluN1/N2A-subtype 1-TMD focused
手法: EM (単粒子) / 解像度: 4.29 Å

EMDB-64285: native GluN1/N2B-subtype1 in closed state
手法: EM (単粒子) / 解像度: 3.93 Å

EMDB-64289: native GluN1/N2A-subtype2-consensus map
手法: EM (単粒子) / 解像度: 6.37 Å

EMDB-64290: native GluN1/N2A-subtype2-TMD focused map
手法: EM (単粒子) / 解像度: 4.53 Å

EMDB-64292: native GluN1/N2A-S3-consensus map in the closed state
手法: EM (単粒子) / 解像度: 3.29 Å

EMDB-64294: native GluN1/N2A-S3 TMD focused map in the closed state
手法: EM (単粒子) / 解像度: 3.73 Å

EMDB-64295: native GluN1/N2B receptor consensus map in the closed state
手法: EM (単粒子) / 解像度: 3.37 Å

EMDB-64296: native GluN1/N2B-TMD-focused map in the closed state
手法: EM (単粒子) / 解像度: 4.0 Å

EMDB-64297: native GluN1/N2B/NX-consensus map in the closed state
手法: EM (単粒子) / 解像度: 3.5 Å

EMDB-64298: native GluN1/N2A/NX-TMD-focused map in the closed state
手法: EM (単粒子) / 解像度: 4.22 Å

EMDB-64299: native GluN1/N2B/NX composite map in the closed state
手法: EM (単粒子) / 解像度: 3.5 Å

EMDB-64300: native GluN1_N2A_NX_subtype-consensus map in the closed state
手法: EM (単粒子) / 解像度: 3.58 Å

EMDB-64301: native GluN1_N2A_NX_subtype1_TMD_focused map in the closed state
手法: EM (単粒子) / 解像度: 3.58 Å

EMDB-64302: native GluN1_N2A_NX_subtype1_composite_map in the closed state
手法: EM (単粒子) / 解像度: 3.1 Å

EMDB-64303: native GluN1_N2A_NX_S2_consensus map
手法: EM (単粒子) / 解像度: 3.66 Å

EMDB-64304: native GluN1_N2A_NX_subtype2_TMD_focused
手法: EM (単粒子) / 解像度: 3.94 Å

EMDB-64305: native GluN1_N2A_NX_subtype2_composite map
手法: EM (単粒子) / 解像度: 3.66 Å

EMDB-64306: native GluN1_NX_consensus_map
手法: EM (単粒子) / 解像度: 3.3 Å

EMDB-64307: native GluN1_NX TMD focused map
手法: EM (単粒子) / 解像度: 3.9 Å

EMDB-64308: native GluN1_GluNX composite map
手法: EM (単粒子) / 解像度: 3.3 Å

EMDB-64309: native native NMDA receptor-GluN1/N2B in inactive state TMD focused map
手法: EM (単粒子) / 解像度: 4.55 Å

EMDB-64310: native NMDA receptor-GluN1/N2B in the inactive state consensus map
手法: EM (単粒子) / 解像度: 6.21 Å

EMDB-64311: native NMDA receptor-GluN1/N2A in inactive state consensus map
手法: EM (単粒子) / 解像度: 3.55 Å

EMDB-64313: native NMDA receptor-GluN1/N2A/N2B in inactive state consensus map
手法: EM (単粒子) / 解像度: 3.3 Å

EMDB-64314: native NMDA receptor-GluN1/N2A/N2B in inactive state TMD focused map
手法: EM (単粒子) / 解像度: 3.24 Å

EMDB-64315: native NMDA receptor-GluN1/N2B/NX in the open state consensus map
手法: EM (単粒子) / 解像度: 3.28 Å

EMDB-64316: native NMDA receptor-GluN1/N2B/NX in the open state TMD focused map
手法: EM (単粒子) / 解像度: 3.42 Å

EMDB-64317: native NMDA receptor-GluN1/N2B/NX in the open state
手法: EM (単粒子) / 解像度: 3.28 Å

EMDB-64318: native NMDA receptor-GluN1/N2A in inactive state TMD focused map
手法: EM (単粒子) / 解像度: 3.53 Å

EMDB-64319: native NMDA receptor-GluN1/N2B/NX in inactive state consensus map
手法: EM (単粒子) / 解像度: 3.47 Å

EMDB-64320: native NMDA receptor-GluN1/N2B/NX in inactive state TMD focused map
手法: EM (単粒子) / 解像度: 3.56 Å

EMDB-64321: native NMDA receptor-GluN1/N2B/NX in inactive state
手法: EM (単粒子) / 解像度: 3.47 Å

EMDB-64326: native NMDA receptor-GluN1-N2A-NX consensus map
手法: EM (単粒子) / 解像度: 3.23 Å

EMDB-64327: native NMDA receptor-GlUN1/N2A/NX TMD focused map
手法: EM (単粒子) / 解像度: 3.17 Å

EMDB-64328: native NMDA receptor-GluN1/N2A/NX composite map
手法: EM (単粒子) / 解像度: 3.23 Å

EMDB-64330: native NMDA receptor-GluN1/NX consensus map
手法: EM (単粒子) / 解像度: 3.57 Å

EMDB-64331: native NMDA receptor-GluN1/NX TMD focused map
手法: EM (単粒子) / 解像度: 3.51 Å

EMDB-64332: native NMDA receptor-GluN1/NX composite map
手法: EM (単粒子) / 解像度: 3.57 Å

64337

9un2

EMDB-64337, PDB-9un2:
native NMDAR receptor-GluN1/N2B in the inactive state
手法: EM (単粒子) / 解像度: 4.3 Å

64338

9un3

EMDB-64338, PDB-9un3:
native NMDA receptor-GluN1/N2B in the open state
手法: EM (単粒子) / 解像度: 3.37 Å

64353

9unj

EMDB-64353, PDB-9unj:
native NMDA receptor-GluN1/N2A-S1 in closed state
手法: EM (単粒子) / 解像度: 3.93 Å

64354

9unk

EMDB-64354, PDB-9unk:
native NMDA receptor-GluN1/N2B in the closed state
手法: EM (単粒子) / 解像度: 3.37 Å

64356

9unm

EMDB-64356, PDB-9unm:
native NMDA receptor-GluN1/N2A-S2 in the closed state
手法: EM (単粒子) / 解像度: 6.37 Å

64357

9unn

EMDB-64357, PDB-9unn:
native NMDA receptor-GluN1/N2A-S3 in the closed state
手法: EM (単粒子) / 解像度: 3.29 Å

64358

9uno

EMDB-64358, PDB-9uno:
native NMDA receptor-GluN1/N2A in the inactive state
手法: EM (単粒子) / 解像度: 3.55 Å

64359

9unp

EMDB-64359, PDB-9unp:
native NMDA receptor-GluN1/N2A/N2B-S2 in the closed state
手法: EM (単粒子) / 解像度: 3.27 Å

64360

9unq

EMDB-64360, PDB-9unq:
native NMDA receptor-GluN1/N2A/2B in inactive state
手法: EM (単粒子) / 解像度: 3.2 Å

64361

9unr

EMDB-64361, PDB-9unr:
native NMDA receptor-GluN1/N2A/N2B-S1 in the closed state
手法: EM (単粒子) / 解像度: 2.98 Å

化合物

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-アセチル-β-D-グルコサミン

ChemComp-GLY:
GLYCINE / グリシン

ChemComp-GLU:
GLUTAMIC ACID / グルタミン酸

ChemComp-JC9:
(2~{S})-2-(2-chlorophenyl)-2-(methylamino)cyclohexan-1-one / (S)-ケタミン

由来
  • mus musculus (ハツカネズミ)
  • Homo sapiens (ヒト)
キーワード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

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