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- EMDB-36338: Cryo-EM structure of GluN1-2A NMDAR in complex with human Fab2G7 ... -

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Entry
Database: EMDB / ID: EMD-36338
TitleCryo-EM structure of GluN1-2A NMDAR in complex with human Fab2G7 in one fab conformation
Map data
Sample
  • Cell: Cryo-EM structure of GluN1-2A NMDAR in complex with human Fab28
    • Protein or peptide: Glutamate receptor ionotropic, NMDA 2A
    • Protein or peptide: Glutamate receptor ionotropic, NMDA 1
    • Protein or peptide: Fab2G7 Heavy Chain
    • Protein or peptide: Fab2G7 Light Chain
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
KeywordsNMDAR / autoimmune encephalitis / MEMBRANE PROTEIN
Function / homology
Function and homology information


glycine-gated cation channel activity / excitatory chemical synaptic transmission / directional locomotion / Synaptic adhesion-like molecules / serotonin metabolic process / protein localization to postsynaptic membrane / response to glycine / propylene metabolic process / sleep / Assembly and cell surface presentation of NMDA receptors ...glycine-gated cation channel activity / excitatory chemical synaptic transmission / directional locomotion / Synaptic adhesion-like molecules / serotonin metabolic process / protein localization to postsynaptic membrane / response to glycine / propylene metabolic process / sleep / Assembly and cell surface presentation of NMDA receptors / regulation of monoatomic cation transmembrane transport / NMDA glutamate receptor activity / NMDA selective glutamate receptor complex / Neurexins and neuroligins / glutamate binding / ligand-gated sodium channel activity / neurotransmitter receptor complex / glutamate receptor signaling pathway / calcium ion transmembrane import into cytosol / protein heterotetramerization / glycine binding / startle response / positive regulation of reactive oxygen species biosynthetic process / monoatomic cation transmembrane transport / dopamine metabolic process / Negative regulation of NMDA receptor-mediated neuronal transmission / Unblocking of NMDA receptors, glutamate binding and activation / positive regulation of calcium ion transport into cytosol / Long-term potentiation / excitatory synapse / monoatomic cation transport / regulation of neuronal synaptic plasticity / monoatomic ion channel complex / positive regulation of excitatory postsynaptic potential / synaptic cleft / positive regulation of synaptic transmission, glutamatergic / calcium ion homeostasis / MECP2 regulates neuronal receptors and channels / glutamate-gated calcium ion channel activity / neurogenesis / EPHB-mediated forward signaling / sensory perception of pain / sodium ion transmembrane transport / ionotropic glutamate receptor signaling pathway / Ras activation upon Ca2+ influx through NMDA receptor / cytoplasmic vesicle membrane / synaptic membrane / response to amphetamine / regulation of membrane potential / excitatory postsynaptic potential / transmitter-gated monoatomic ion channel activity involved in regulation of postsynaptic membrane potential / synaptic transmission, glutamatergic / protein catabolic process / postsynaptic density membrane / brain development / visual learning / negative regulation of protein catabolic process / regulation of synaptic plasticity / calcium ion transmembrane transport / response to wounding / memory / long-term synaptic potentiation / terminal bouton / synaptic vesicle / signaling receptor activity / amyloid-beta binding / presynaptic membrane / RAF/MAP kinase cascade / response to ethanol / chemical synaptic transmission / dendritic spine / postsynaptic membrane / learning or memory / calmodulin binding / neuron projection / postsynaptic density / positive regulation of apoptotic process / response to xenobiotic stimulus / dendrite / calcium ion binding / synapse / 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: 4.3 Å
AuthorsWang H / Zhu S
Funding support China, 5 items
OrganizationGrant numberCountry
Other government2022ZD0212700 China
Other governmentLG 202106-02 China
Other government2017YFA0505700 China
Other governmentXDBS01020000 China
Other government2018SHZDZX05 China
CitationJournal: Nat Struct Mol Biol / Year: 2024
Title: Structural basis for antibody-mediated NMDA receptor clustering and endocytosis in autoimmune encephalitis.
Authors: Han Wang / Chun Xie / Bo Deng / Jinjun Ding / Na Li / Zengwei Kou / Mengmeng Jin / Jie He / Qinrui Wang / Han Wen / Jinbao Zhang / Qinming Zhou / Sheng Chen / Xiangjun Chen / Ti-Fei Yuan / Shujia Zhu /
Abstract: Antibodies against N-methyl-D-aspartate receptors (NMDARs) are most frequently detected in persons with autoimmune encephalitis (AE) and used as diagnostic biomarkers. Elucidating the structural ...Antibodies against N-methyl-D-aspartate receptors (NMDARs) are most frequently detected in persons with autoimmune encephalitis (AE) and used as diagnostic biomarkers. Elucidating the structural basis of monoclonal antibody (mAb) binding to NMDARs would facilitate the development of targeted therapy for AE. Here, we reconstructed nanodiscs containing green fluorescent protein-fused NMDARs to label and sort individual immune B cells from persons with AE and further cloned and identified mAbs against NMDARs. This allowed cryo-electron microscopy analysis of NMDAR-Fab complexes, revealing that autoantibodies bind to the R1 lobe of the N-terminal domain of the GluN1 subunit. Small-angle X-ray scattering studies demonstrated NMDAR-mAb stoichiometry of 2:1 or 1:2, structurally suitable for mAb-induced clustering and endocytosis of NMDARs. Importantly, these mAbs reduced the surface NMDARs and NMDAR-mediated currents, without tonically affecting NMDAR channel gating. These structural and functional findings imply that the design of neutralizing antibody binding to the R1 lobe of NMDARs represents a potential therapy for AE treatment.
History
DepositionMay 29, 2023-
Header (metadata) releaseJun 5, 2024-
Map releaseJun 5, 2024-
UpdateDec 25, 2024-
Current statusDec 25, 2024Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_36338.png

Downloads & links

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Map

FileDownload / File: emd_36338.map.gz / Format: CCP4 / Size: 178 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

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AxesZ (Sec.)Y (Row.)X (Col.)
1.08 Å/pix.
x 360 pix.
= 388.8 Å		1.08 Å/pix.
x 360 pix.
= 388.8 Å		1.08 Å/pix.
x 360 pix.
= 388.8 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.08 Å
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Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.014
Minimum - Maximum-0.010216889 - 0.049304444
Average (Standard dev.)0.000167622 (±0.0022097903)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions360360360
Spacing360360360
CellA=B=C: 388.80002 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_36338_half_map_1.map
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Half map: #2

Fileemd_36338_half_map_2.map
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Sample components

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Entire : Cryo-EM structure of GluN1-2A NMDAR in complex with human Fab28

EntireName: Cryo-EM structure of GluN1-2A NMDAR in complex with human Fab28
Components
  • Cell: Cryo-EM structure of GluN1-2A NMDAR in complex with human Fab28
    • Protein or peptide: Glutamate receptor ionotropic, NMDA 2A
    • Protein or peptide: Glutamate receptor ionotropic, NMDA 1
    • Protein or peptide: Fab2G7 Heavy Chain
    • Protein or peptide: Fab2G7 Light Chain
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: Cryo-EM structure of GluN1-2A NMDAR in complex with human Fab28

SupramoleculeName: Cryo-EM structure of GluN1-2A NMDAR in complex with human Fab28
type: cell / ID: 1 / Parent: 0 / Macromolecule list: #1-#4
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Glutamate receptor ionotropic, NMDA 2A

MacromoleculeName: Glutamate receptor ionotropic, NMDA 2A / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 94.136016 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MGRVGYWTLL VLPALLVWRG PAPSAAAEKG PPALNIAVML GHSHDVTERE LRTLWGPEQA AGLPLDVNVV ALLMNRTDPK SLITHVCDL MSGARIHGLV FGDDTDQEAV AQMLDFISSH TFVPILGIHG GASMIMADKD PTSTFFQFGA SIQQQATVML K IMQDYDWH ...String:
MGRVGYWTLL VLPALLVWRG PAPSAAAEKG PPALNIAVML GHSHDVTERE LRTLWGPEQA AGLPLDVNVV ALLMNRTDPK SLITHVCDL MSGARIHGLV FGDDTDQEAV AQMLDFISSH TFVPILGIHG GASMIMADKD PTSTFFQFGA SIQQQATVML K IMQDYDWH VFSLVTTIFP GYREFISFVK TTVDNSFVGW DMQNVITLDT SFEDAKTQVQ LKKIHSSVIL LYCSKDEAVL IL SEARSLG LTGYDFFWIV PSLVSGNTEL IPKEFPSGLI SVSYDDWDYS LEARVRDGIG ILTTAASSML EKFSYIPEAK ASC YGQMER PEVPMHTLHP FMVNVTWDGK DLSFTEEGYQ VHPRLVVIVL NKDREWEKVG KWENHTLSLR HAVWPRYKSF SDCE PDDNH LSIVTLEEAP FVIVEDIDPL TETCVRNTVP CRKFVKINNS TNEGMNVKKC CKGFCIDILK KLSRTVKFTY DLYLV TNGK HGKKVNNVWN GMIGEVVYQR AVMAVGSLTI NEERSEVVDF SVPFVETGIS VMVSRSNGTV SPSAFLEPFS ASVWVM MFV MLLIVSAIAV FVFEYFSPVG YNRNLAKGKA PHGPSFTIGK AIWLLWGLVF NNSVPVQNPK GTTSKIMVSV WAFFAVI FL ASYTANLAAF MIQEEFVDQV TGLSDKKFQR PHDYSPPFRF GTVPNGSTER NIRNNYPYMH QYMTKFNQKG VEDALVSL K TGKLDAFIYD AAVLNYKAGR DEGCKLVTIG SGYIFATTGY GIALQKGSPW KRQIDLALLQ FVGDGEMEEL ETLWLTGIC HNEKNEVMSS QLDIDNMAGV FYMLAAAMAL SLITFIWEHL F

UniProtKB: Glutamate receptor ionotropic, NMDA 2A

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Macromolecule #2: Glutamate receptor ionotropic, NMDA 1

MacromoleculeName: Glutamate receptor ionotropic, NMDA 1 / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 95.236078 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MSTMRLLTLA LLFSCSVARA ACDPKIVNIG AVLSTRKHEQ MFREAVNQAN KRHGSWKIQL NATSVTHKPN AIQMALSVCE DLISSQVYA ILVSHPPTPN DHFTPTPVSY TAGFYRIPVL GLTTRMSIYS DKSIHLSFLR TVPPYSHQSS VWFEMMRVYS W NHIILLVS ...String:
MSTMRLLTLA LLFSCSVARA ACDPKIVNIG AVLSTRKHEQ MFREAVNQAN KRHGSWKIQL NATSVTHKPN AIQMALSVCE DLISSQVYA ILVSHPPTPN DHFTPTPVSY TAGFYRIPVL GLTTRMSIYS DKSIHLSFLR TVPPYSHQSS VWFEMMRVYS W NHIILLVS DDHEGRAAQK RLETLLEERE SKAEKVLQFD PGTKNVTALL MEAKELEARV IILSASEDDA ATVYRAAAML NM TGSGYVW LVGEREISGN ALRYAPDGIL GLQLINGKNE SAHISDAVGV VAQAVHELLE KENITDPPRG CVGNTNIWKT GPL FKRVLM SSKYADGVTG RVEFNEDGDR KFANYSIMNL QNRKLVQVGI YNGTHVIPND RKIIWPGGET EKPRGYQMST RLKI VTIHQ EPFVYVKPTL SDGTCKEEFT VNGDPVKKVI CTGPNDTSPG SPRHTVPQCC YGFCIDLLIK LARTMNFTYE VHLVA DGKF GTQERVNNSN KKEWNGMMGE LLSGQADMIV APLTINNERA QYIEFSKPFK YQGLTILVKK EIPRSTLDSF MQPFQS TLW LLVGLSVHVV AVMLYLLDRF SPFGRFKVNS EEEEEDALTL SSAMWFSWGV LLNSGIGEGA PRSFSARILG MVWAGFA MI IVASYTANLA AFLVLDRPEE RITGINDPRL RNPSDKFIYA TVKQSSVDIY FRRQVELSTM YRHMEKHNYE SAAEAIQA V RDNKLHAFIW DSAVLEFEAS QKCDLVTTGE LFFRSGFGIG MRKDSPWKQN VSLSILKSHE NGFMEDLDKT WVRYQECDS RSNAPATLTF ENMAGVFMLV AGGIVAGIFL IFIEIAYKRH KDARRKQ

UniProtKB: Glutamate receptor ionotropic, NMDA 1

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Macromolecule #3: Fab2G7 Heavy Chain

MacromoleculeName: Fab2G7 Heavy Chain / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 26.893043 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MDWTWSILFL VAAPTGAHSQ VQLVQSGAEV RKPGASVKVS CRASGYSFTG YYVHWVRQAP GQGLEWLGWI NPNTGGTDYS QKFQGRVTM TRDTSITTAY VELSSLISDD TAVYYCARDA TGAASSPFDY WGQGTLVTVS SASTKGPSVF PLAPSSKSTS G GTAALGCL ...String:
MDWTWSILFL VAAPTGAHSQ VQLVQSGAEV RKPGASVKVS CRASGYSFTG YYVHWVRQAP GQGLEWLGWI NPNTGGTDYS QKFQGRVTM TRDTSITTAY VELSSLISDD TAVYYCARDA TGAASSPFDY WGQGTLVTVS SASTKGPSVF PLAPSSKSTS G GTAALGCL VKDYFPEPVT VSWNSGALTS GVHTFPAVLQ SSGLYSLSSV VTVPSSSLGT QTYICNVNHK PSNTKVDKRV EP KSCDKTH TCPPCP

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Macromolecule #4: Fab2G7 Light Chain

MacromoleculeName: Fab2G7 Light Chain / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 25.764998 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MDMRVPAQLL GLLLLWLRGA RCDIQMTQSP STLSASVGDR VTITCRASQS ISSWLAWYQQ RPGQAPKLLI YMASTLQTGV PSRFSGSGS GTEFTLTISS LQPDDFATYY CQHYKSYSFG PGTKVDIKRT VAAPSVFIFP PSDEQLKSGT ASVVCLLNNF Y PREAKVQW ...String:
MDMRVPAQLL GLLLLWLRGA RCDIQMTQSP STLSASVGDR VTITCRASQS ISSWLAWYQQ RPGQAPKLLI YMASTLQTGV PSRFSGSGS GTEFTLTISS LQPDDFATYY CQHYKSYSFG PGTKVDIKRT VAAPSVFIFP PSDEQLKSGT ASVVCLLNNF Y PREAKVQW KVDNALQSGN SQESVTEQDS KDSTYSLSST LTLSKADYEK HKVYACEVTH QGLSSPVTKS FNRGEC

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Macromolecule #6: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 6 / Number of copies: 8 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

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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: 8
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 281 K / Instrument: FEI VITROBOT MARK III

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 70.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.5 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: INSILICO MODEL
Final reconstructionResolution.type: BY AUTHOR / Resolution: 4.3 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION / Number images used: 148340
Initial angle assignmentType: ANGULAR RECONSTITUTION / Software - Name: RELION
Final angle assignmentType: ANGULAR RECONSTITUTION / Software - Name: RELION
Final 3D classificationSoftware - Name: RELION

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