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- PDB-10en: SK3D-Matured in complex with GluN1-GluN2B, full refinement -

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Basic information

Entry
Database: PDB / ID: 10en
TitleSK3D-Matured in complex with GluN1-GluN2B, full refinement
Components
  • Glutamate receptor
  • Isoform 4 of Glutamate receptor ionotropic, NMDA 1
  • SK3D Heavy chain
  • SK3D Light chain
KeywordsSIGNALING PROTEIN/Immune System / NMDAR / 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 / NMDA glutamate receptor activity / NMDA selective glutamate receptor complex / ligand-gated sodium channel activity / protein heterotetramerization / glycine binding ...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 / NMDA glutamate receptor activity / NMDA selective glutamate receptor complex / ligand-gated sodium channel activity / protein heterotetramerization / glycine binding / ligand-gated monoatomic ion channel activity / glutamate-gated calcium ion channel activity / ionotropic glutamate receptor signaling pathway / sodium ion transmembrane transport / regulation of membrane potential / regulation of synaptic plasticity / postsynaptic density membrane / calcium ion transmembrane transport / signaling receptor activity / chemical synaptic transmission / response to ethanol / postsynaptic membrane / neuron projection / synapse / dendrite / endoplasmic reticulum membrane / metal ion binding / plasma membrane
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 / Glutamate receptor ionotropic, NMDA 1
Similarity search - Component
Biological speciesHomo sapiens (human)
Mus musculus (house mouse)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.7 Å
AuthorsKleeman, S.O. / Furukawa, H.F.
Funding support United States, 1items
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, 2026Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 25, 2026Provider: repository / Type: Initial release
Revision 1.0Mar 25, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Mar 25, 2026Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Mar 25, 2026Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Mar 25, 2026Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Mar 25, 2026Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Apr 8, 2026Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _em_admin.last_update
Revision 1.1Apr 8, 2026Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Database references / Experimental summary / Data content type: EM metadata / EM metadata / EM metadata / Category: citation / citation_author / em_admin
Data content type: EM metadata / EM metadata ...EM metadata / EM metadata / EM metadata / EM metadata / EM metadata / EM metadata / EM metadata / EM metadata / EM metadata / EM metadata
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Isoform 4 of Glutamate receptor ionotropic, NMDA 1
B: Glutamate receptor
C: Isoform 4 of Glutamate receptor ionotropic, NMDA 1
D: Glutamate receptor
E: SK3D Light chain
F: SK3D Heavy chain
I: SK3D Light chain
J: SK3D Heavy chain


Theoretical massNumber of molelcules
Total (without water)411,2588
Polymers411,2588
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein Isoform 4 of Glutamate receptor ionotropic, NMDA 1 / GluN1 / Glutamate [NMDA] receptor subunit zeta-1 / N-methyl-D-aspartate receptor 1 / N-methyl-D- ...GluN1 / Glutamate [NMDA] receptor subunit zeta-1 / N-methyl-D-aspartate receptor 1 / N-methyl-D-aspartate receptor subunit NR1 / NMD-R1


Mass: 91827.914 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GRIN1, NMDAR1 / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q5R1P0
#2: Protein Glutamate receptor


Mass: 88673.234 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GRIN2B / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: A0A8B7RCM5
#3: Antibody SK3D Light chain


Mass: 12008.365 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Cell line (production host): Ric15 / Production host: Homo sapiens (human)
#4: Antibody SK3D Heavy chain


Mass: 13119.579 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Cell line (production host): Ric15 / Production host: Homo sapiens (human)
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: SK3D IgG in complex with GluN1-GluN2B NMDAR protein / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.4
SpecimenConc.: 5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2200 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 71.7 e/Å2 / Film or detector model: GATAN K3 BIOCONTINUUM (6k x 4k)

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Processing

EM software
IDNameCategory
1cryoSPARCparticle selection
13cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.7 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 130398 / Symmetry type: POINT

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