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- EMDB-43530: Human GluN1-2A IgG 003-102 splayed conformation -

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Entry
Database: EMDB / ID: EMD-43530
TitleHuman GluN1-2A IgG 003-102 splayed conformation
Map data
Sample
  • Complex: Human GluN1-2A IgG 003-102 splayed 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
KeywordsReceptor / antibody / ion channel / MEMBRANE-IMMUNE SYSTEM complex
Function / homology
Function and homology information


glycine-gated cation channel activity / excitatory chemical synaptic transmission / directional locomotion / serotonin metabolic process / Synaptic adhesion-like molecules / protein localization to postsynaptic membrane / response to glycine / propylene metabolic process / sleep / regulation of monoatomic cation transmembrane transport ...glycine-gated cation channel activity / excitatory chemical synaptic transmission / directional locomotion / serotonin metabolic process / Synaptic adhesion-like molecules / protein localization to postsynaptic membrane / response to glycine / propylene metabolic process / sleep / regulation of monoatomic cation transmembrane transport / Assembly and cell surface presentation of NMDA receptors / NMDA glutamate receptor activity / Neurexins and neuroligins / neurotransmitter receptor complex / NMDA selective glutamate receptor complex / ligand-gated sodium channel activity / calcium ion transmembrane import into cytosol / glutamate receptor signaling pathway / glutamate binding / protein heterotetramerization / glycine binding / positive regulation of reactive oxygen species biosynthetic process / positive regulation of calcium ion transport into cytosol / Negative regulation of NMDA receptor-mediated neuronal transmission / startle response / dopamine metabolic process / Unblocking of NMDA receptors, glutamate binding and activation / monoatomic cation transmembrane transport / regulation of neuronal synaptic plasticity / Long-term potentiation / monoatomic cation transport / excitatory synapse / positive regulation of excitatory postsynaptic potential / monoatomic ion channel complex / synaptic cleft / calcium ion homeostasis / MECP2 regulates neuronal receptors and channels / glutamate-gated calcium ion channel activity / neurogenesis / sensory perception of pain / EPHB-mediated forward signaling / sodium ion transmembrane transport / response to amphetamine / Ras activation upon Ca2+ influx through NMDA receptor / ionotropic glutamate receptor signaling pathway / cytoplasmic vesicle membrane / positive regulation of synaptic transmission, glutamatergic / regulation of membrane potential / excitatory postsynaptic potential / transmitter-gated monoatomic ion channel activity involved in regulation of postsynaptic membrane potential / synaptic transmission, glutamatergic / synaptic membrane / protein catabolic process / postsynaptic density membrane / terminal bouton / brain development / visual learning / negative regulation of protein catabolic process / calcium ion transmembrane transport / regulation of synaptic plasticity / memory / response to wounding / long-term synaptic potentiation / synaptic vesicle / signaling receptor activity / amyloid-beta binding / presynaptic membrane / RAF/MAP kinase cascade / chemical synaptic transmission / dendritic spine / response to ethanol / postsynaptic membrane / learning or memory / calmodulin binding / neuron projection / postsynaptic density / positive regulation of apoptotic process / response to xenobiotic stimulus / synapse / dendrite / calcium ion binding / endoplasmic reticulum membrane / protein-containing complex binding / glutamatergic synapse / 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: 4.42 Å
AuthorsMichalski K / Furukawa H
Funding support United States, 3 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Mental Health (NIH/NIMH)NS11745 United States
National Institutes of Health/National Institute of Mental Health (NIH/NIMH)MH085926 United States
National Institutes of Health/National Institute of Mental Health (NIH/NIMH)F32MH121061 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-
UpdateDec 25, 2024-
Current statusDec 25, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_43530.png

Downloads & links

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Map

FileDownload / File: emd_43530.map.gz / Format: CCP4 / Size: 244.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

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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

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.856 Å
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Histogram (log scale)
Contour LevelBy AUTHOR: 0.0248
Minimum - Maximum-0.15623431 - 0.26276392
Average (Standard dev.)0.000114827744 (±0.008562912)
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_43530_half_map_1.map
Projections & Slices
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Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_43530_half_map_2.map
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Sample components

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Entire : Human GluN1-2A IgG 003-102 splayed conformation

EntireName: Human GluN1-2A IgG 003-102 splayed conformation
Components
  • Complex: Human GluN1-2A IgG 003-102 splayed 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 IgG 003-102 splayed conformation

SupramoleculeName: Human GluN1-2A IgG 003-102 splayed 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: 91.837 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: IVNIGAVLST RKHEQMFREA VNQANKRHGS WKIQLNATSV THKPNAIQMA LSVCEDLISS QVYAILVSHP PTPNDHFTPT PVSYTAGFY RIPVLGLTTR MSIYSDKSIH LSFLRTVPPY SHQSSVWFEM MRVYSWNHII LLVSDDHEGR AAQKRLETLL E ERESKAEK ...String:
IVNIGAVLST RKHEQMFREA VNQANKRHGS WKIQLNATSV THKPNAIQMA LSVCEDLISS QVYAILVSHP PTPNDHFTPT PVSYTAGFY RIPVLGLTTR MSIYSDKSIH LSFLRTVPPY SHQSSVWFEM MRVYSWNHII LLVSDDHEGR AAQKRLETLL E ERESKAEK VLQFDPGTKN VTALLMEAKE LEARVIILSA SEDDAATVYR AAAMLNMTGS GYVWLVGERE ISGNALRYAP DG ILGLQLI NGKNESAHIS DAVGVVAQAV HELLEKENIT DPPRGCVGNT NIWKTGPLFK RVLMSSKYAD GVTGRVEFNE DGD RKFANY SIMNLQRRKL VQVGIYNGTH VIPNDRKIIW PGGETEKPRG YQMSTRLKIV TIHQEPFVYV KPTLSDGTCK EEFT VNGDP VKKVICTGPN DTSPGSPRHT VPQCCYGFCI DLLIKLARTM NFTYEVHLVA DGKFGTQERV NNSNKKEWNG MMGEL LSGQ ADMIVAPLTI NNERAQYIEF SKPFKYQGLT ILVKKEIPRS TLDSFMQPFQ STLWLLVGLS VHVVAVMLYL LDRFSP FGR FKVNSEEEEE DALTLSSAMW FSWGVLLNSG IGEGAPRSFS ARILGMVWAG FAMIIVASYT ANLAAFLVLD RPEERIT GI NDPRLRNPSD KFIYATVKQS SVDIYFRRQV ELSTMYRHME KHNYESAAEA IQAVRDNKLH AFIWDSAVLE FEASQKCD L VTTGELFFRS GFGIGMRKDS PWKQNVSLSI LKSHENGFME DLDKTWVRYQ ECDSRSNAPA TLTFENMAGV FMLVAGGIV AGIFLIFIEI AYKRHK

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: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 12.678098 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
LQLQESGPGL VKPSQTLSLT CTVSGGSISS SNWWSWVRQP PGKGLEWIGE IYHSGNTNYN PSLKSRVTVS VDKSKNQFSL KLTSVTAAD TAVYYCARDV SGGVNWFDPW GQGTLVTV

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Macromolecule #5: 003-102 Light

MacromoleculeName: 003-102 Light / type: protein_or_peptide / ID: 5 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 11.681605 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
NFMLTQPHSV SESPGKTVTI SCTRSSGSIA SNYVQWYQQR PGSAPTTVIY EDNQRPSGVP DRFSGSIDSS SNSASLTISG LKTEDEADY 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
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 / Nominal defocus max: 2.2 µm / Nominal defocus min: 0.8 µm

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Image processing

Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 4.42 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 101287
Initial angle assignmentType: OTHER
Final angle assignmentType: OTHER

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