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- EMDB-75121: SK5A-Matured apo state in complex with GluN1-GluN2B, full refinement -

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Basic information

Entry
Database: EMDB / ID: EMD-75121
TitleSK5A-Matured apo state in complex with GluN1-GluN2B, full refinement
Map dataSK5A-Matured apo state in complex with GluN1-GluN2B, full refinement
Sample
  • Complex: SK3D IgG in complex with GluN1-GluN2B NMDAR protein
    • Protein or peptide: Isoform 4 of Glutamate receptor ionotropic, NMDA 1
    • Protein or peptide: Glutamate receptor ionotropic, NMDA 2B
    • Protein or peptide: Light chain
    • Protein or peptide: Heavy chain
KeywordsNMDAR / antibody / SIGNALING PROTEIN / SIGNALING PROTEIN-Immune System complex
Function / homology
Function and homology information


Unblocking of NMDA receptors, glutamate binding and activation / RAF/MAP kinase cascade / Synaptic adhesion-like molecules / Assembly and cell surface presentation of NMDA receptors / EPHB-mediated forward signaling / excitatory chemical synaptic transmission / Activated NTRK2 signals through FYN / Synaptic adhesion-like molecules / Assembly and cell surface presentation of NMDA receptors / negative regulation of dendritic spine maintenance ...Unblocking of NMDA receptors, glutamate binding and activation / RAF/MAP kinase cascade / Synaptic adhesion-like molecules / Assembly and cell surface presentation of NMDA receptors / EPHB-mediated forward signaling / excitatory chemical synaptic transmission / Activated NTRK2 signals through FYN / Synaptic adhesion-like molecules / Assembly and cell surface presentation of NMDA receptors / negative regulation of dendritic spine maintenance / Neurexins and neuroligins / regulation of monoatomic cation transmembrane transport / NMDA glutamate receptor activity / NMDA selective glutamate receptor complex / glutamate binding / glutamate receptor signaling pathway / ligand-gated sodium channel activity / calcium ion transmembrane import into cytosol / protein heterotetramerization / glycine binding / Negative regulation of NMDA receptor-mediated neuronal transmission / Unblocking of NMDA receptors, glutamate binding and activation / monoatomic cation transmembrane transport / Long-term potentiation / regulation of neuronal synaptic plasticity / ligand-gated monoatomic ion channel activity / MECP2 regulates neuronal receptors and channels / positive regulation of synaptic transmission, glutamatergic / EPHB-mediated forward signaling / glutamate-gated calcium ion channel activity / ionotropic glutamate receptor signaling pathway / Ras activation upon Ca2+ influx through NMDA receptor / ligand-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential / positive regulation of excitatory postsynaptic potential / sodium ion transmembrane transport / synaptic membrane / transmitter-gated monoatomic ion channel activity involved in regulation of postsynaptic membrane potential / synaptic transmission, glutamatergic / regulation of membrane potential / excitatory postsynaptic potential / brain development / regulation of synaptic plasticity / postsynaptic density membrane / calcium ion transmembrane transport / late endosome / long-term synaptic potentiation / amyloid-beta binding / RAF/MAP kinase cascade / signaling receptor activity / chemical synaptic transmission / cytoskeleton / response to ethanol / learning or memory / postsynaptic membrane / lysosome / neuron projection / postsynaptic density / synapse / dendrite / endoplasmic reticulum membrane / cell surface / zinc ion binding / metal ion binding / plasma membrane / cytoplasm
Similarity search - Function
Glutamate [NMDA] receptor, epsilon subunit, C-terminal / N-methyl D-aspartate receptor 2B3 C-terminus / : / : / Ionotropic glutamate receptor, metazoa / Ligated ion channel L-glutamate- and glycine-binding site / Ligand-gated ion channel / Ionotropic glutamate receptor, L-glutamate and glycine-binding domain / Ligated ion channel L-glutamate- and glycine-binding site / : ...Glutamate [NMDA] receptor, epsilon subunit, C-terminal / N-methyl D-aspartate receptor 2B3 C-terminus / : / : / Ionotropic glutamate receptor, metazoa / Ligated ion channel L-glutamate- and glycine-binding site / Ligand-gated ion channel / Ionotropic glutamate receptor, L-glutamate and glycine-binding domain / Ligated ion channel L-glutamate- and glycine-binding site / : / Ionotropic glutamate receptor / Eukaryotic homologues of bacterial periplasmic substrate binding proteins. / Receptor, ligand binding region / Receptor family ligand binding region / Periplasmic binding protein-like I
Similarity search - Domain/homology
Glutamate receptor ionotropic, NMDA 2B / Glutamate receptor ionotropic, NMDA 1
Similarity search - Component
Biological speciesHomo sapiens (human) / Mus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 4.08 Å
AuthorsKleeman SO / Furukawa HF
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Mental Health (NIH/NIMH)MH085926 United States
CitationJournal: Nature / Year: 2026
Title: Ectopic NMDAR expression in cancer unmasks germline-encoded autoimmunity.
Authors: Sam O Kleeman / Kevin Michalski / Xiang Zhao / Ruben Steigerwald / Miriam Ferrer / Llewelyn Levett / Ethan Ertel / Austin Schultz / Noriko Simorowski / Pamela Moody / Tse-Luen Wee / Cristina ...Authors: Sam O Kleeman / Kevin Michalski / Xiang Zhao / Ruben Steigerwald / Miriam Ferrer / Llewelyn Levett / Ethan Ertel / Austin Schultz / Noriko Simorowski / Pamela Moody / Tse-Luen Wee / Cristina Valente / Sharon Fox / Mateusz Makuch / Selina Thomsen / Ruby Harrison / Claire Regan / Jonathan Preall / Qing Gao / Dennis Thomas / Jill Habel / Rachel Rubino / Sarosh Irani / Hiro Furukawa / Tobias Janowitz /
Abstract: Autoimmunity and anti-cancer immunity lie on the same biological continuum, but their link remains obscure. The paraneoplastic neurological syndrome ANRE (anti-NMDA receptor (NMDAR) encephalitis) is ...Autoimmunity and anti-cancer immunity lie on the same biological continuum, but their link remains obscure. The paraneoplastic neurological syndrome ANRE (anti-NMDA receptor (NMDAR) encephalitis) is a paradigm for their connectivity, given that intratumoural NMDAR expression is correlated with the generation of anti-NMDAR antibodies. Here we verify ectopic expression of GluN1 and GluN2B NMDAR subunits in triple-negative breast cancer (TNBC) and model this using orthotopic TNBC tumours with inducible expression of GluN1-GluN2B NMDARs. We show that NMDAR expression is sufficient to induce the recruitment of B cells and their affinity maturation, consistent with an integrated adaptive immune response. Reconstruction of extended intratumoural B cell phylogenies and cryogenic electron microscopy structural analyses demonstrate that affinity-matured hypermutated and class-switched antibodies emerged from pre-existing germline-configuration lower-affinity anti-NMDAR antibodies. Distinct matured antibodies targeted specific epitopes and induced conformational rearrangements within the NMDAR amino-terminal domain, predictive of their functional effects, ranging from inhibition to potentiation. Passive transfer of an NMDAR-potentiating antibody caused autonomic dysregulation and lowered the seizure threshold in healthy female mice, recapitulating key diagnostic criteria of ANRE. We further identify a correlation between intratumoural NMDAR expression and anti-NMDAR antibody titres in patients with TNBC. Taken together, our data establish a direct connection between intratumoural NMDAR expression, antibody maturation and the onset of autoimmunity. These findings suggest that germline-encoded anti-NMDAR antibodies contribute to immune surveillance but can also trigger autoimmune disease after maturation, revealing a mechanistic trade-off between cancer immunity and neurotoxicity.
History
DepositionJan 15, 2026-
Header (metadata) releaseMar 25, 2026-
Map releaseMar 25, 2026-
UpdateApr 8, 2026-
Current statusApr 8, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_75121.png

Downloads & links

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Map

FileDownload / File: emd_75121.map.gz / Format: CCP4 / Size: 244.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationSK5A-Matured apo state in complex with GluN1-GluN2B, full refinement
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
1 Å/pix.
x 400 pix.
= 400. Å		1 Å/pix.
x 400 pix.
= 400. Å		1 Å/pix.
x 400 pix.
= 400. Å

Surface

Projections

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.07
Minimum - Maximum-0.3151775 - 0.45273024
Average (Standard dev.)-0.00028712527 (±0.009144462)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions400400400
Spacing400400400
CellA=B=C: 400.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: Half Map A

Fileemd_75121_half_map_1.map
AnnotationHalf Map A
Projections & Slices
AxesZYX

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Slices (1/2)
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Histogram

Histogram (log scale)

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Half map: Half Map B

Fileemd_75121_half_map_2.map
AnnotationHalf Map B
Projections & Slices
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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : SK3D IgG in complex with GluN1-GluN2B NMDAR protein

EntireName: SK3D IgG in complex with GluN1-GluN2B NMDAR protein
Components
  • Complex: SK3D IgG in complex with GluN1-GluN2B NMDAR protein
    • Protein or peptide: Isoform 4 of Glutamate receptor ionotropic, NMDA 1
    • Protein or peptide: Glutamate receptor ionotropic, NMDA 2B
    • Protein or peptide: Light chain
    • Protein or peptide: Heavy chain

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Supramolecule #1: SK3D IgG in complex with GluN1-GluN2B NMDAR protein

SupramoleculeName: SK3D IgG in complex with GluN1-GluN2B NMDAR protein / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Isoform 4 of Glutamate receptor ionotropic, NMDA 1

MacromoleculeName: Isoform 4 of Glutamate receptor ionotropic, NMDA 1 / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 91.827914 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: KIVNIGAVLS TRKHEQMFRE AVNQANKRHG SWKIQLNATS VTHKPNAIQM ALSVCEDLIS SQVYAILVSH PPTPNDHFTP TPVSYTAGF YRIPVLGLTT RMSIYSDKSI HLSFLRTVPP YSHQSSVWFE MMRVYSWNHI ILLVSDDHEG RAAQKRLETL L EERESKAE ...String:
KIVNIGAVLS TRKHEQMFRE AVNQANKRHG SWKIQLNATS VTHKPNAIQM ALSVCEDLIS SQVYAILVSH PPTPNDHFTP TPVSYTAGF YRIPVLGLTT RMSIYSDKSI HLSFLRTVPP YSHQSSVWFE MMRVYSWNHI ILLVSDDHEG RAAQKRLETL L EERESKAE KVLQFDPGTK NVTALLMEAR ELEARVIILS ASEDDAATVY RAAAMLNMTG SGYVWLVGER EISGNALRYA PD GIIGLQL INGKNESAHI SDAVGVVAQA VHELLEKENI TDPPRGCVGN TNIWKTGPLF KRVLMSSKYA DGVTGRVEFN EDG DRKFAN YSIMNLQNRK LVQVGIYNGT HVIPNDRKII WPGGETEKPR GYQMSTRLKI VTIHQEPFVY VKPTLSDGTC KEEF TVNGD PVKKVICTGP NDTSPGSPRH TVPQCCYGFC IDLLIKLART MNFTYEVHLV ADGKFGTQER VNNSNKKEWN GMMGE LLSG QADMIVAPLT INNERAQYIE FSKPFKYQGL TILVKKEIPR STLDSFMNPF QSTLWLLVGL SVHVVAVMLY LLDRFS PFG RFKVNSEEEE EDALTLSSAM WFSWGVLLNS GIGEGAPRSF SARILGMVWA GFAMIIVASY TANLAAFLVL DRPEERI TG INDPRLRNPS DKFIYATVKQ SSVDIYFRRQ VELSTMYRHM EKHNYESAAE AIQAVRDNKL HAFIWDSAVL EFEASQKC D LVTTGELFFR SGFGIGMRKD SPWKQNVSLS ILKSHENGFM EDLDKTWVRY QECDSRSNAP ATLTFENMAG VFMIVAGGI VAGIFLIFIE IAYKSRA

UniProtKB: Glutamate receptor ionotropic, NMDA 1

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Macromolecule #2: Glutamate receptor ionotropic, NMDA 2B

MacromoleculeName: Glutamate receptor ionotropic, NMDA 2B / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 88.673234 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: FHHLSVVPRV ELVAMNETDP KSIITRICDL MSDRKIQGVV FADDTDQEAI AQILDFISAQ TLTPILGIHG GSSMIMADKD ESSMFFQFG PSIEQQASVM LNIMEEYDWY IFSIVTTYFP GYQDFVNKIR STIENSFVGW ELEEVLLLDM SLDDGDSKIQ N QLKKLQSP ...String:
FHHLSVVPRV ELVAMNETDP KSIITRICDL MSDRKIQGVV FADDTDQEAI AQILDFISAQ TLTPILGIHG GSSMIMADKD ESSMFFQFG PSIEQQASVM LNIMEEYDWY IFSIVTTYFP GYQDFVNKIR STIENSFVGW ELEEVLLLDM SLDDGDSKIQ N QLKKLQSP IILLYCTKEE ATYIFEVANS VGLTGYGYTW IVPSLVAGDT DTVPSEFPTG LISVSYDEWD YGLPARVRDG IA IITTAAS DMLSEHSFIP EPKSSCYNTH EKRIYQSNML NRYLINVTFE GRNLSFSEDG YQMHPKLVII LLNKERKWER VGK WKDKSL QMKYYVWPRM CPETEEQEDD HLSIVTLEEA PFVIVESVDP LSGTCMRNTV PCEKRIVTEN KTDEEPGYIK KCCK GFCID ILKKISKSVK FTYDLYLVTN GKHGKKINGT WNGMIGEVVM KRAYMAVGSL TINEERSEVV DFSVPFIETG ISVMV SRSN GTVSPSAFLE PFSADVWVMM FVMLLIVSAV AVFVFEYFSP VGYNRCLADG REPGGPSFTI GKAIWLLWGL VFNNSV PVQ NPKGTTSKIM VSVWAFFAVI FLASYTANLA AFMIQEEYVD QVSGLSDKKF QRPNDFSPPF RFGTVPNGST ERNIRNN YA EMHAYMGKFN QRGVDDALLS LKTGKLDAFI YDAAVLNYMA GRDEGCKLVT IGSGKVFAST GYGIAIQKDS GWKRQVDL A ILQLFGDGEM EELEALWLTG ICHNEKNEVM SSQLDIDNMA GVFYMLGAAM ALSLITFISE HLFYWQ

UniProtKB: Glutamate receptor ionotropic, NMDA 2B

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Macromolecule #3: Light chain

MacromoleculeName: Light chain / type: protein_or_peptide / ID: 3 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 11.642848 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
DIQMTQSPSS LSASLGERVS LTCRASQDIG STLIWLQQEP DGTIKRLIYA TSSLDSGVPK RFSGSRSGSD YSLTISSLES EDFVDYYCL QYASSPYTFG GGTKLEIK

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Macromolecule #4: Heavy chain

MacromoleculeName: Heavy chain / type: protein_or_peptide / ID: 4 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 12.66998 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
EVQLQQSGAE LVKPGASVKL SCTASGFNIK DTYIHWVKQR PEQGLEWIGR IDPANGNTKY DPKFQGKATV TADTSSNAAY LHLSSLTSE DTAVYYCARS YDSFAYWGQG TLVTVSA

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration5 mg/mL
BufferpH: 7.4
VitrificationCryogen name: ETHANE / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 BIOCONTINUUM (6k x 4k) / Average electron dose: 71.7 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.2 µm / Nominal defocus min: 0.8 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

7saa

Final reconstructionResolution.type: BY AUTHOR / Resolution: 4.08 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 114482
Initial angle assignmentType: RANDOM ASSIGNMENT
Final angle assignmentType: OTHER / Details: cryoSPARC refinement

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