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- EMDB-43537: Human GluN1-2A with IgG 003-102 WT conformation -

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Basic information

Entry
Database: EMDB / ID: EMD-43537
TitleHuman GluN1-2A with IgG 003-102 WT conformation
Map data
Sample
  • Complex: Human GluN1-2A with IgG 003-102 WT conformation
    • Protein or peptide: Glutamate receptor ionotropic, NMDA 1
    • Protein or peptide: Glutamate receptor ionotropic, NMDA 2A
    • Protein or peptide: Glutamate receptor ionotropic, NMDA 1
    • Protein or peptide: 003-102 Heavy
    • Protein or peptide: 003-102 Light
KeywordsChannel / heterotetramer / receptor / antibody / MEMBRANE PROTEIN-IMMUNE SYSTEM complex
Function / homology
Function and homology information


excitatory chemical synaptic transmission / directional locomotion / Synaptic adhesion-like molecules / serotonin metabolic process / activation of cysteine-type endopeptidase activity / protein localization to postsynaptic membrane / propylene metabolic process / response to glycine / sleep / regulation of monoatomic cation transmembrane transport ...excitatory chemical synaptic transmission / directional locomotion / Synaptic adhesion-like molecules / serotonin metabolic process / activation of cysteine-type endopeptidase activity / protein localization to postsynaptic membrane / propylene metabolic process / response to glycine / sleep / regulation of monoatomic cation transmembrane transport / Assembly and cell surface presentation of NMDA receptors / NMDA glutamate receptor activity / Neurexins and neuroligins / NMDA selective glutamate receptor complex / calcium ion transmembrane import into cytosol / glutamate binding / glutamate receptor signaling pathway / protein heterotetramerization / positive regulation of calcium ion transport into cytosol / positive regulation of reactive oxygen species biosynthetic process / glycine binding / startle response / Negative regulation of NMDA receptor-mediated neuronal transmission / Unblocking of NMDA receptors, glutamate binding and activation / dopamine metabolic process / monoatomic cation transmembrane transport / regulation of neuronal synaptic plasticity / monoatomic cation transport / Long-term potentiation / excitatory synapse / ligand-gated monoatomic ion channel activity / positive regulation of excitatory postsynaptic potential / calcium ion homeostasis / synaptic cleft / MECP2 regulates neuronal receptors and channels / glutamate-gated calcium ion channel activity / EPHB-mediated forward signaling / sensory perception of pain / response to amphetamine / ionotropic glutamate receptor signaling pathway / Ras activation upon Ca2+ influx through NMDA receptor / neurogenesis / positive regulation of synaptic transmission, glutamatergic / regulation of membrane potential / excitatory postsynaptic potential / synaptic transmission, glutamatergic / synaptic membrane / long-term synaptic potentiation / transmitter-gated monoatomic ion channel activity involved in regulation of postsynaptic membrane potential / postsynaptic density membrane / brain development / visual learning / cytoplasmic vesicle membrane / protein catabolic process / regulation of synaptic plasticity / negative regulation of protein catabolic process / terminal bouton / memory / response to wounding / synaptic vesicle / signaling receptor activity / presynaptic membrane / amyloid-beta binding / RAF/MAP kinase cascade / chemical synaptic transmission / postsynaptic membrane / response to ethanol / dendritic spine / postsynaptic density / learning or memory / calmodulin binding / neuron projection / positive regulation of apoptotic process / response to xenobiotic stimulus / glutamatergic synapse / dendrite / calcium ion binding / synapse / endoplasmic reticulum membrane / protein-containing complex binding / cell surface / positive regulation of transcription by RNA polymerase II / zinc 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 / Ionotropic glutamate receptor, L-glutamate and glycine-binding domain / Ligated ion channel L-glutamate- and glycine-binding site / Ligand-gated ion channel / : ...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 / Ionotropic glutamate receptor, L-glutamate and glycine-binding domain / Ligated ion channel L-glutamate- and glycine-binding site / Ligand-gated ion channel / : / 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 1 / Glutamate receptor ionotropic, NMDA 2A
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.84 Å
AuthorsMichalski K / Furukawa H
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Mental Health (NIH/NIMH)NS11745, MH085926, F32MH121061, NS113632 United States
CitationJournal: Nat Struct Mol Biol / Year: 2024
Title: Structural and functional mechanisms of anti-NMDAR autoimmune encephalitis.
Authors: Kevin Michalski / Taha Abdulla / Sam Kleeman / Lars Schmidl / Ricardo Gómez / Noriko Simorowski / Francesca Vallese / Harald Prüss / Manfred Heckmann / Christian Geis / Hiro Furukawa /
Abstract: Autoantibodies against neuronal membrane proteins can manifest in autoimmune encephalitis, inducing seizures, cognitive dysfunction and psychosis. Anti-N-methyl-D-aspartate receptor (NMDAR) ...Autoantibodies against neuronal membrane proteins can manifest in autoimmune encephalitis, inducing seizures, cognitive dysfunction and psychosis. Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is the most dominant autoimmune encephalitis; however, insights into how autoantibodies recognize and alter receptor functions remain limited. Here we determined structures of human and rat NMDARs bound to three distinct patient-derived antibodies using single-particle electron cryo-microscopy. These antibodies bind different regions within the amino-terminal domain of the GluN1 subunit. Through electrophysiology, we show that all three autoantibodies acutely and directly reduced NMDAR channel functions in primary neurons. Antibodies show different stoichiometry of binding and antibody-receptor complex formation, which in one antibody, 003-102, also results in reduced synaptic localization of NMDARs. These studies demonstrate mechanisms of diverse epitope recognition and direct channel regulation of anti-NMDAR autoantibodies underlying autoimmune encephalitis.
History
DepositionJan 29, 2024-
Header (metadata) releaseSep 11, 2024-
Map releaseSep 11, 2024-
UpdateNov 6, 2024-
Current statusNov 6, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_43537.png

Downloads & links

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Map

FileDownload / File: emd_43537.map.gz / Format: CCP4 / Size: 244.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.86 Å/pix.
x 400 pix.
= 342.4 Å		0.86 Å/pix.
x 400 pix.
= 342.4 Å		0.86 Å/pix.
x 400 pix.
= 342.4 Å

Surface

Projections

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.856 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0509
Minimum - Maximum-0.42556703 - 0.74315536
Average (Standard dev.)0.00021360796 (±0.015868807)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions400400400
Spacing400400400
CellA=B=C: 342.4 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_43537_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_43537_half_map_2.map
Projections & Slices
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Histogram

Histogram (log scale)

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Sample components

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Entire : Human GluN1-2A with IgG 003-102 WT conformation

EntireName: Human GluN1-2A with IgG 003-102 WT conformation
Components
  • Complex: Human GluN1-2A with IgG 003-102 WT conformation
    • Protein or peptide: Glutamate receptor ionotropic, NMDA 1
    • Protein or peptide: Glutamate receptor ionotropic, NMDA 2A
    • Protein or peptide: Glutamate receptor ionotropic, NMDA 1
    • Protein or peptide: 003-102 Heavy
    • Protein or peptide: 003-102 Light

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Supramolecule #1: Human GluN1-2A with IgG 003-102 WT conformation

SupramoleculeName: Human GluN1-2A with IgG 003-102 WT conformation / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Glutamate receptor ionotropic, NMDA 1

MacromoleculeName: Glutamate receptor ionotropic, NMDA 1 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 91.68075 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: VNIGAVLSTR KHEQMFREAV NQANKRHGSW KIQLNATSVT HKPNAIQMAL SVCEDLISSQ VYAILVSHPP TPNDHFTPTP VSYTAGFYR IPVLGLTTRM SIYSDKSIHL SFLRTVPPYS HQSSVWFEMM RVYSWNHIIL LVSDDHEGRA AQKRLETLLE E RESKAEKV ...String:
VNIGAVLSTR KHEQMFREAV NQANKRHGSW KIQLNATSVT HKPNAIQMAL SVCEDLISSQ VYAILVSHPP TPNDHFTPTP VSYTAGFYR IPVLGLTTRM SIYSDKSIHL SFLRTVPPYS HQSSVWFEMM RVYSWNHIIL LVSDDHEGRA AQKRLETLLE E RESKAEKV LQFDPGTKNV TALLMEAKEL EARVIILSAS EDDAATVYRA AAMLNMTGSG YVWLVGEREI SGNALRYAPD GI LGLQLIN GKNESAHISD AVGVVAQAVH ELLEKENITD PPRGCVGNTN IWKTGPLFKR VLMSSKYADG VTGRVEFNED GDR KFANYS IMNLQNRKLV QVGIYNGTHV IPNDRKIIWP GGETEKPRGY QMSTRLKIVT IHQEPFVYVK PTLSDGTCKE EFTV NGDPV KKVICTGPND TSPGSPRHTV PQCCYGFCID LLIKLARTMN FTYEVHLVAD GKFGTQERVN NSNKKEWNGM MGELL SGQA DMIVAPLTIN NERAQYIEFS KPFKYQGLTI LVKKEIPRST LDSFMQPFQS TLWLLVGLSV HVVAVMLYLL DRFSPF GRF KVNSEEEEED ALTLSSAMWF SWGVLLNSGI GEGAPRSFSA RILGMVWAGF AMIIVASYTA NLAAFLVLDR PEERITG IN DPRLRNPSDK FIYATVKQSS VDIYFRRQVE LSTMYRHMEK HNYESAAEAI QAVRDNKLHA FIWDSAVLEF EASQKCDL V TTGELFFRSG FGIGMRKDSP WKQNVSLSIL KSHENGFMED LDKTWVRYQE CDSRSNAPAT LTFENMAGVF MLVAGGIVA GIFLIFIEIA YKRHK

UniProtKB: Glutamate receptor ionotropic, NMDA 1

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Macromolecule #2: Glutamate receptor ionotropic, NMDA 2A

MacromoleculeName: Glutamate receptor ionotropic, NMDA 2A / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 90.684805 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: LNIAVMLGHS HDVTERELRT LWGPEQAAGL PLDVNVVALL MNRTDPKSLI THVCDLMSGA RIHGLVFGDD TDQEAVAQML DFISSHTFV PILGIHGGAS MIMADKDPTS TFFQFGASIQ QQATVMLKIM QDYDWHVFSL VTTIFPGYRE FISFVKTTVD N SFVGWDMQ ...String:
LNIAVMLGHS HDVTERELRT LWGPEQAAGL PLDVNVVALL MNRTDPKSLI THVCDLMSGA RIHGLVFGDD TDQEAVAQML DFISSHTFV PILGIHGGAS MIMADKDPTS TFFQFGASIQ QQATVMLKIM QDYDWHVFSL VTTIFPGYRE FISFVKTTVD N SFVGWDMQ NVITLDTSFE DAKTQVQLKK IHSSVILLYC SKDEAVLILS EARSLGLTGY DFFWIVPSLV SGNTELIPKE FP SGLISVS YDDWDYSLEA RVRDGIGILT TAASSMLEKF SYIPEAKASC YGQMERPEVP MHTLHPFMVN VTWDGKDLSF TEE GYQVHP RLVVIVLNKD REWEKVGKWE NHTLSLRHAV WPRYKSFSDC EPDDNHLSIV TLEEAPFVIV EDIDPLTETC VRNT VPCRK FVKINNSTNE GMNVKKCCKG FCIDILKKLS RTVKFTYDLY LVTNGKHGKK VNNVWNGMIG EVVYQRAVMA VGSLT INEE RSEVVDFSVP FVETGISVMV SRSNGTVSPS AFLEPFSASV WVMMFVMLLI VSAIAVFVFE YFSPVGYNRC LADGRE PGG PSFTIGKAIW LLWGLVFNNS VPVQNPKGTT SKIMVSVWAF FAVIFLASYT ANLAAFMIQE EFVDQVTGLS DKKFQRP HD YSPPFRFGTV PNGSTERNIR NNYPYMHQYM TKFNQKGVED ALVSLKTGKL DAFIYDAAVL NYKAGRDEGC KLVTIGSG Y IFATTGYGIA LQKGSPWKRQ IDLALLQFVG DGEMEELETL WLTGICHNEK NEVMSSQLDI DNMAGVFYML AAAMALSLI TFIWEHLF

UniProtKB: Glutamate receptor ionotropic, NMDA 2A

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Macromolecule #3: Glutamate receptor ionotropic, NMDA 1

MacromoleculeName: Glutamate receptor ionotropic, NMDA 1 / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 91.737867 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: VNIGAVLSTR KHEQMFREAV NQANKRHASW KIQLNATSVT HKPNAIQMAL SVCEDLISSQ VYAILVSHPP TPNDHFTPTP VSYTAGFYR IPVLGLTTRM SIYSDKSIHL SFLRTVPPYS HQSSVWFEMM RVYSWNHIIL LVSDDHEGRA AQKRLETLLE E RESKAEKV ...String:
VNIGAVLSTR KHEQMFREAV NQANKRHASW KIQLNATSVT HKPNAIQMAL SVCEDLISSQ VYAILVSHPP TPNDHFTPTP VSYTAGFYR IPVLGLTTRM SIYSDKSIHL SFLRTVPPYS HQSSVWFEMM RVYSWNHIIL LVSDDHEGRA AQKRLETLLE E RESKAEKV LQFDPGTKNV TALLMEAKEL EARVIILSAS EDDAATVYRA AAMLNMTGSG YVWLVGEREI SGNALRYAPD GI LGLQLIN GKNESAHISD AVGVVAQAVH ELLEKENITD PPRGCVGNTN IWKTGPLFKR VLMSSKYADG VTGRVEFNED GDR KFANYS IMNLQRRKLV QVGIYNGTHV IPNDRKIIWP GGETEKPRGY QMSTRLKIVT IHQEPFVYVK PTLSDGTCKE EFTV NGDPV KKVICTGPND TSPGSPRHTV PQCCYGFCID LLIKLARTMN FTYEVHLVAD GKFGTQERVN NSNKKEWNGM MGELL SGQA DMIVAPLTIN NERAQYIEFS KPFKYQGLTI LVKKEIPRST LDSFMQPFQS TLWLLVGLSV HVVAVMLYLL DRFSPF GRF KVNSEEEEED ALTLSSAMWF SWGVLLNSGI GEGAPRSFSA RILGMVWAGF AMIIVASYTA NLAAFLVLDR PEERITG IN DPRLRNPSDK FIYATVKQSS VDIYFRRQVE LSTMYRHMEK HNYESAAEAI QAVRDNKLHA FIWDSAVLEF EASQKCDL V TTGELFFRSG FGIGMRKDSP WKQNVSLSIL KSHENGFMED LDKTWVRYQE CDSRSNAPAT LTFENMAGVF MLVAGGIVA GIFLIFIEIA YKRHK

UniProtKB: Glutamate receptor ionotropic, NMDA 1

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Macromolecule #4: 003-102 Heavy

MacromoleculeName: 003-102 Heavy / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 25.338205 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: LQLQESGPGL VKPSQTLSLT CTVSGGSISS SNWWSWVRQP PGKGLEWIGE IYHSGNTNYN PSLKSRVTVS VDKSKNQFSL KLTSVTAAD TAVYYCARDV SGGVNWFDPW GQGTLVTVLQ LQESGPGLVK PSQTLSLTCT VSGGSISSSN WWSWVRQPPG K GLEWIGEI ...String:
LQLQESGPGL VKPSQTLSLT CTVSGGSISS SNWWSWVRQP PGKGLEWIGE IYHSGNTNYN PSLKSRVTVS VDKSKNQFSL KLTSVTAAD TAVYYCARDV SGGVNWFDPW GQGTLVTVLQ LQESGPGLVK PSQTLSLTCT VSGGSISSSN WWSWVRQPPG K GLEWIGEI YHSGNTNYNP SLKSRVTVSV DKSKNQFSLK LTSVTAADTA VYYCARDVSG GVNWFDPWGQ GTLVTV

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Macromolecule #5: 003-102 Light

MacromoleculeName: 003-102 Light / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 23.345229 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: NFMLTQPHSV SESPGKTVTI SCTRSSGSIA SNYVQWYQQR PGSAPTTVIY EDNQRPSGVP DRFSGSIDSS SNSASLTISG LKTEDEADY YCQSYDSSTV VFGGGTKLTV NFMLTQPHSV SESPGKTVTI SCTRSSGSIA SNYVQWYQQR PGSAPTTVIY E DNQRPSGV ...String:
NFMLTQPHSV SESPGKTVTI SCTRSSGSIA SNYVQWYQQR PGSAPTTVIY EDNQRPSGVP DRFSGSIDSS SNSASLTISG LKTEDEADY YCQSYDSSTV VFGGGTKLTV NFMLTQPHSV SESPGKTVTI SCTRSSGSIA SNYVQWYQQR PGSAPTTVIY E DNQRPSGV PDRFSGSIDS SSNSASLTIS GLKTEDEADY YCQSYDSSTV VFGGGTKLTV

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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

BufferpH: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 60.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: OTHER / Imaging mode: OTHER / Cs: 2.7 mm / 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

Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.84 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 133432
Initial angle assignmentType: OTHER
Final angle assignmentType: OTHER

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