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- EMDB-43538: Human GluN1-2A with IgG 007-168 -

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Basic information

Entry
Database: EMDB / ID: EMD-43538
TitleHuman GluN1-2A with IgG 007-168
Map data
Sample
  • Complex: Human GluN1-2A with IgG 007-168
    • Protein or peptide: 007-168 Heavy
    • Protein or peptide: 007-168 Light
    • Protein or peptide: Glutamate receptor ionotropic, NMDA 1
    • Protein or peptide: Glutamate receptor ionotropic, NMDA 2A
    • Protein or peptide: Glutamate receptor ionotropic, NMDA 1
KeywordsChannel / heterotetramer / receptor / antibody / MEMBRANE PROTEIN-IMMUNE SYSTEM complex
Function / homology
Function and homology information


excitatory chemical synaptic transmission / Synaptic adhesion-like molecules / propylene metabolic process / response to glycine / Assembly and cell surface presentation of NMDA receptors / regulation of monoatomic cation transmembrane transport / NMDA glutamate receptor activity / Neurexins and neuroligins / NMDA selective glutamate receptor complex / calcium ion transmembrane import into cytosol ...excitatory chemical synaptic transmission / Synaptic adhesion-like molecules / propylene metabolic process / response to glycine / Assembly and cell surface presentation of NMDA receptors / regulation of monoatomic cation transmembrane transport / NMDA glutamate receptor activity / Neurexins and neuroligins / NMDA selective glutamate receptor complex / calcium ion transmembrane import into cytosol / glutamate binding / protein heterotetramerization / positive regulation of reactive oxygen species biosynthetic process / positive regulation of calcium ion transport into cytosol / glycine binding / Negative regulation of NMDA receptor-mediated neuronal transmission / Unblocking of NMDA receptors, glutamate binding and activation / monoatomic cation transmembrane transport / regulation of neuronal synaptic plasticity / monoatomic cation transport / Long-term potentiation / positive regulation of excitatory postsynaptic potential / ligand-gated monoatomic ion channel activity / excitatory synapse / calcium ion homeostasis / synaptic cleft / glutamate-gated calcium ion channel activity / EPHB-mediated forward signaling / Ras activation upon Ca2+ influx through NMDA receptor / ionotropic glutamate receptor signaling pathway / positive regulation of synaptic transmission, glutamatergic / regulation of membrane potential / excitatory postsynaptic potential / synaptic membrane / long-term synaptic potentiation / visual learning / brain development / regulation of synaptic plasticity / terminal bouton / synaptic vesicle / signaling receptor activity / amyloid-beta binding / RAF/MAP kinase cascade / chemical synaptic transmission / postsynaptic membrane / response to ethanol / dendritic spine / postsynaptic density / calmodulin binding / neuron projection / calcium ion binding / dendrite / synapse / endoplasmic reticulum membrane / protein-containing complex binding / cell surface / positive regulation of transcription by RNA polymerase II / 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 2A / Glutamate receptor ionotropic, NMDA 1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.99 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-
UpdateSep 18, 2024-
Current statusSep 18, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_43538.png

Downloads & links

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Map

FileDownload / File: emd_43538.map.gz / Format: CCP4 / Size: 325 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 440 pix.
= 376.64 Å		0.86 Å/pix.
x 440 pix.
= 376.64 Å		0.86 Å/pix.
x 440 pix.
= 376.64 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.856 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0508
Minimum - Maximum-0.32103518 - 0.6339187
Average (Standard dev.)0.0004708373 (±0.013406346)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions440440440
Spacing440440440
CellA=B=C: 376.64 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_43538_half_map_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_43538_half_map_2.map
Projections & Slices
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Histogram (log scale)

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Sample components

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Entire : Human GluN1-2A with IgG 007-168

EntireName: Human GluN1-2A with IgG 007-168
Components
  • Complex: Human GluN1-2A with IgG 007-168
    • Protein or peptide: 007-168 Heavy
    • Protein or peptide: 007-168 Light
    • Protein or peptide: Glutamate receptor ionotropic, NMDA 1
    • Protein or peptide: Glutamate receptor ionotropic, NMDA 2A
    • Protein or peptide: Glutamate receptor ionotropic, NMDA 1

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Supramolecule #1: Human GluN1-2A with IgG 007-168

SupramoleculeName: Human GluN1-2A with IgG 007-168 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: 007-168 Heavy

MacromoleculeName: 007-168 Heavy / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 22.52225 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: QVQLVQSGAE AKKPGESLKI SCKASGYSFT TFWIGWVRQM PGSGLEWIGI IYPGDSDTRY SPSFQGHVTI SADRSTSTAY LQWSSLKAS DTAMYYCARS AVFDYWGQGT LVTVSSASTK GPSVFPLAPS SGTAALGCLV KDYFPEPVTV SWNSGALTSG V HTFPAVLQ ...String:
QVQLVQSGAE AKKPGESLKI SCKASGYSFT TFWIGWVRQM PGSGLEWIGI IYPGDSDTRY SPSFQGHVTI SADRSTSTAY LQWSSLKAS DTAMYYCARS AVFDYWGQGT LVTVSSASTK GPSVFPLAPS SGTAALGCLV KDYFPEPVTV SWNSGALTSG V HTFPAVLQ SSGLYSLSSV VTVPSSSLGT QTYICNVNHK PSNTKVDKKV EPK

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Macromolecule #2: 007-168 Light

MacromoleculeName: 007-168 Light / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 23.455982 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: EIVMTQSPAT LSVSPGGRAT LSCRASQSVS SNLAWYQQKP GQAPRLLIYG ASTRATGIPV RFSGSGSGTE FTLTISSLQS EDFAVYYCQ QYNNWPTSWT FGQGTKVEIK RTVAAPSVFI FPPSDEQLKS GTASVVCLLN NFYPREAKVQ WKVDNALQSG N SQESVTEQ ...String:
EIVMTQSPAT LSVSPGGRAT LSCRASQSVS SNLAWYQQKP GQAPRLLIYG ASTRATGIPV RFSGSGSGTE FTLTISSLQS EDFAVYYCQ QYNNWPTSWT FGQGTKVEIK RTVAAPSVFI FPPSDEQLKS GTASVVCLLN NFYPREAKVQ WKVDNALQSG N SQESVTEQ DSKDSTYSLS STLTLSKADY EKHKVYACEV THQGLSSPVT KSFNRGE

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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: 87.477797 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: DPKIVNIGAV LSTRKHEQMF REAVNQANKR HGSWKIQLNA TSVTHKPNAI QMALSVCEDL ISSQVYAILV SHPPTPNDHF TPTPVSYTA GFYRIPVLGL TTRMSIYSDK SIHLSFLRTV PPYSHQSSVW FEMMRVYSWN HIILLVSDDH EGRAAQKRLE T LLEERESK ...String:
DPKIVNIGAV LSTRKHEQMF REAVNQANKR HGSWKIQLNA TSVTHKPNAI QMALSVCEDL ISSQVYAILV SHPPTPNDHF TPTPVSYTA GFYRIPVLGL TTRMSIYSDK SIHLSFLRTV PPYSHQSSVW FEMMRVYSWN HIILLVSDDH EGRAAQKRLE T LLEERESK AEKVLQFDPG TKNVTALLME AKELEARVII LSASEDDAAT VYRAAAMLNM TGSGYVWLVG EREISGNALR YA PDGILGL QLINGKNESA HISDAVGVVA QAVHELLEKE NITDPPRGCV GNTNIWKTGP LFKRVLMSSK YADGVTGRVE FNE DGDRKF ANYSIMNLQN RKLVQVGIYN GTHVIPNDRK IIWPGGETEK PRGYQMSTRL KIVTIHQEPF VYVKPTLSDG TCKE EFTVN GDPVKKVICT GPNDTSPGSP RHTVPQCCYG FCIDLLIKLA RTMNFTYEVH LVADGKFGTQ ERVNNSNKKE WNGMM GELL SGQADMIVAP LTINNERAQY IEFSKPFKYQ GLTILVKKEI PRSTLDSFMQ PFQSTLWLLV GLSVHVVAVM LYLLDR FSP FGRFKVNSEE EEEDALTLSS AMWFSWGVLL NSGIGEGAPR SFSARILGMV WAGFAMIIVA SYTANLAAFL VLDRPEE RI TGINDPRLRN PSDKFIYATV KQSSVDIYFR RQVELSTMYR HMEKHNYESA AEAIQAVRDN KLHAFIWDSA VLEFEASQ K CDLVTTGELF FRSGFGIGMR KDSPWKQNVS LSILKSHENG FMEDLDKTWV RYQEC

UniProtKB: Glutamate receptor ionotropic, NMDA 1

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Macromolecule #4: Glutamate receptor ionotropic, NMDA 2A

MacromoleculeName: Glutamate receptor ionotropic, NMDA 2A / type: protein_or_peptide / ID: 4 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 86.50793 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

UniProtKB: Glutamate receptor ionotropic, NMDA 2A

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Macromolecule #5: Glutamate receptor ionotropic, NMDA 1

MacromoleculeName: Glutamate receptor ionotropic, NMDA 1 / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 87.534922 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: DPKIVNIGAV LSTRKHEQMF REAVNQANKR HASWKIQLNA TSVTHKPNAI QMALSVCEDL ISSQVYAILV SHPPTPNDHF TPTPVSYTA GFYRIPVLGL TTRMSIYSDK SIHLSFLRTV PPYSHQSSVW FEMMRVYSWN HIILLVSDDH EGRAAQKRLE T LLEERESK ...String:
DPKIVNIGAV LSTRKHEQMF REAVNQANKR HASWKIQLNA TSVTHKPNAI QMALSVCEDL ISSQVYAILV SHPPTPNDHF TPTPVSYTA GFYRIPVLGL TTRMSIYSDK SIHLSFLRTV PPYSHQSSVW FEMMRVYSWN HIILLVSDDH EGRAAQKRLE T LLEERESK AEKVLQFDPG TKNVTALLME AKELEARVII LSASEDDAAT VYRAAAMLNM TGSGYVWLVG EREISGNALR YA PDGILGL QLINGKNESA HISDAVGVVA QAVHELLEKE NITDPPRGCV GNTNIWKTGP LFKRVLMSSK YADGVTGRVE FNE DGDRKF ANYSIMNLQR RKLVQVGIYN GTHVIPNDRK IIWPGGETEK PRGYQMSTRL KIVTIHQEPF VYVKPTLSDG TCKE EFTVN GDPVKKVICT GPNDTSPGSP RHTVPQCCYG FCIDLLIKLA RTMNFTYEVH LVADGKFGTQ ERVNNSNKKE WNGMM GELL SGQADMIVAP LTINNERAQY IEFSKPFKYQ GLTILVKKEI PRSTLDSFMQ PFQSTLWLLV GLSVHVVAVM LYLLDR FSP FGRFKVNSEE EEEDALTLSS AMWFSWGVLL NSGIGEGAPR SFSARILGMV WAGFAMIIVA SYTANLAAFL VLDRPEE RI TGINDPRLRN PSDKFIYATV KQSSVDIYFR RQVELSTMYR HMEKHNYESA AEAIQAVRDN KLHAFIWDSA VLEFEASQ K CDLVTTGELF FRSGFGIGMR KDSPWKQNVS LSILKSHENG FMEDLDKTWV RYQEC

UniProtKB: Glutamate receptor ionotropic, NMDA 1

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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: 3.99 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 119725
Initial angle assignmentType: OTHER
Final angle assignmentType: OTHER

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