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- EMDB-43541: Human GluN1-2B with Fab 007-168 Local refinement of ATD -

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Basic information

Entry
Database: EMDB / ID: EMD-43541
TitleHuman GluN1-2B with Fab 007-168 Local refinement of ATD
Map data
Sample
  • Complex: Human GluN1-2B with Fab 007-168 Local refinement of ATD
    • Protein or peptide: Glutamate receptor ionotropic, NMDA 1
    • Protein or peptide: 007-168 Heavy
    • Protein or peptide: 007-168 Light
    • Protein or peptide: Glutamate receptor ionotropic, NMDA 2B
KeywordsReceptor / antibody / ion channel / MEMBRANE PROTEIN-IMMUNE SYSTEM complex
Function / homology
Function and homology information


excitatory chemical synaptic transmission / Activated NTRK2 signals through FYN / positive regulation of cysteine-type endopeptidase activity / Synaptic adhesion-like molecules / negative regulation of dendritic spine maintenance / propylene metabolic process / response to glycine / regulation of monoatomic cation transmembrane transport / Assembly and cell surface presentation of NMDA receptors / NMDA glutamate receptor activity ...excitatory chemical synaptic transmission / Activated NTRK2 signals through FYN / positive regulation of cysteine-type endopeptidase activity / Synaptic adhesion-like molecules / negative regulation of dendritic spine maintenance / propylene metabolic process / response to glycine / 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 / 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 / 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 / ligand-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential / EPHB-mediated forward signaling / ionotropic glutamate receptor signaling pathway / Ras activation upon Ca2+ influx through NMDA receptor / 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 / regulation of synaptic plasticity / terminal bouton / late endosome / synaptic vesicle / signaling receptor activity / amyloid-beta binding / RAF/MAP kinase cascade / chemical synaptic transmission / postsynaptic membrane / response to ethanol / dendritic spine / lysosome / postsynaptic density / learning or memory / cytoskeleton / calmodulin binding / neuron projection / 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 2B
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.69 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 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-
UpdateOct 16, 2024-
Current statusOct 16, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_43541.png

Downloads & links

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Map

FileDownload / File: emd_43541.map.gz / Format: CCP4 / Size: 303.3 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.86 Å/pix.
x 430 pix.
= 368.08 Å		0.86 Å/pix.
x 430 pix.
= 368.08 Å		0.86 Å/pix.
x 430 pix.
= 368.08 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: 0.103
Minimum - Maximum-1.0762062 - 1.5457541
Average (Standard dev.)0.0006724378 (±0.017290961)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions430430430
Spacing430430430
CellA=B=C: 368.08002 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_43541_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_43541_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 GluN1-2B with Fab 007-168 Local refinement of ATD

EntireName: Human GluN1-2B with Fab 007-168 Local refinement of ATD
Components
  • Complex: Human GluN1-2B with Fab 007-168 Local refinement of ATD
    • Protein or peptide: Glutamate receptor ionotropic, NMDA 1
    • Protein or peptide: 007-168 Heavy
    • Protein or peptide: 007-168 Light
    • Protein or peptide: Glutamate receptor ionotropic, NMDA 2B

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Supramolecule #1: Human GluN1-2B with Fab 007-168 Local refinement of ATD

SupramoleculeName: Human GluN1-2B with Fab 007-168 Local refinement of ATD
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: 41.549199 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: DPKIVNIGAV LSTRKHEQMF REAVNQANKR HGSWKIQLNA TSVTHKPNAI QMALSVCEDL ISSQVYAILV SHPPTPNDHF TPTPVSYTA GFYRIPVLGL TTRMSIYSDK SIHLSFLRTV PPYSHQSSVW FEMMRVYNWN HIILLVSDDH EGRAAQKRLE T LLEERESK ...String:
DPKIVNIGAV LSTRKHEQMF REAVNQANKR HGSWKIQLNA TSVTHKPNAI QMALSVCEDL ISSQVYAILV SHPPTPNDHF TPTPVSYTA GFYRIPVLGL TTRMSIYSDK SIHLSFLRTV PPYSHQSSVW FEMMRVYNWN HIILLVSDDH EGRAAQKRLE T LLEERESK AEKVLQFDPG TKNVTALLME ARELEARVII LSASEDDAAT VYRAAAMLNM TGSGYVWLVG EREISGNALR YA PDGIIGL QLINGKNESA HISDAVGVVA QAVHELLEKE NITDPPRGCV GNTNIWKTGP LFKRVLMSSK YADGVTGRVE FNE DGDRKF AQYSIMNLQN RKLVQVGIYN GTHVIPNDRK IIWPGGETEK PRGYQ

UniProtKB: Glutamate receptor ionotropic, NMDA 1

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Macromolecule #2: 007-168 Heavy

MacromoleculeName: 007-168 Heavy / type: protein_or_peptide / ID: 2 / Number of copies: 1 / 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 #3: 007-168 Light

MacromoleculeName: 007-168 Light / type: protein_or_peptide / ID: 3 / Number of copies: 1 / 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 FGQGTKLEIK RTAAAPSVFI FPPSDEQLKS GTASVVCLLN NFYPREAKVQ WKVDNALQSG N SQESVTEQ ...String:
EIVMTQSPAT LSVSPGGRAT LSCRASQSVS SNLAWYQQKP GQAPRLLIYG ASTRATGIPV RFSGSGSGTE FTLTISSLQS EDFAVYYCQ QYNNWPTSWT FGQGTKLEIK RTAAAPSVFI FPPSDEQLKS GTASVVCLLN NFYPREAKVQ WKVDNALQSG N SQESVTEQ DSKDSTYSLS STLTLSKADY EKHKLYACEV THQGLSSPVT KSFNRGE

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Macromolecule #4: Glutamate receptor ionotropic, NMDA 2B

MacromoleculeName: Glutamate receptor ionotropic, NMDA 2B / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 40.358699 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: SAPSIGIAVI LVGTSDEVAI KDAHEKDDFH HLSVVPRVEL VAMNETDPKS IITRICDLMS DRKIQGVVFA DDTDQEAIAQ ILDFISAQT LTPILGIHGG SSMIMADKDE SSMFFQFGPS IEQQASVMLN IMEEYDWYIF SIVTTYFPGY QDFVNKIRST I ENSFVGWE ...String:
SAPSIGIAVI LVGTSDEVAI KDAHEKDDFH HLSVVPRVEL VAMNETDPKS IITRICDLMS DRKIQGVVFA DDTDQEAIAQ ILDFISAQT LTPILGIHGG SSMIMADKDE SSMFFQFGPS IEQQASVMLN IMEEYDWYIF SIVTTYFPGY QDFVNKIRST I ENSFVGWE LEEVLLLDMS LDDGDSKIQN QLKKLQSPII LLYCTKEEAT YIFEVANSVG LTGYGYTWIV PSLVAGDTDT VP SEFPTGL ISVSYDEWDY GLPARVRDGI AIITTAASDM LSEHSFIPEP KSSCYNTHEK RIYQSNMLNR YLINVTFEGR DLS FSEEGY QMHPKLVIIL LNKERKWERV GKWKDKSLQM K

UniProtKB: Glutamate receptor ionotropic, NMDA 2B

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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 / 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: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.69 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 270651
Initial angle assignmentType: OTHER
Final angle assignmentType: OTHER

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