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- EMDB-16227: Hexameric human IgG3 Fc complex -

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Basic information

Entry
Database: EMDB / ID: EMD-16227
TitleHexameric human IgG3 Fc complex
Map dataSubtomogram average of IgG3-Fc hexamer formed on lipid bilayers
Sample
  • Complex: Fc domain of human IgG3
    • Protein or peptide: FLJ00385 protein (Fragment)
    • Protein or peptide: FLJ00385 protein (Fragment)
KeywordsIgG3 / antibody / Fc hexamer / IMMUNE SYSTEM
Function / homology
Function and homology information


immunoglobulin complex / adaptive immune response / plasma membrane
Similarity search - Function
: / Immunoglobulin/major histocompatibility complex, conserved site / Immunoglobulins and major histocompatibility complex proteins signature. / Immunoglobulin C-Type / Immunoglobulin C1-set / Immunoglobulin C1-set domain / Ig-like domain profile. / Immunoglobulin-like domain / Immunoglobulin-like domain superfamily / Immunoglobulin-like fold
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
Methodsubtomogram averaging / cryo EM / Resolution: 14.0 Å
AuthorsAbendstein L / Sharp TH
Funding supportEuropean Union, Netherlands, 3 items
OrganizationGrant numberCountry
European Research Council (ERC)759517European Union
Netherlands Organisation for Scientific Research (NWO)OCENW.KLEIN.291 Netherlands
Netherlands Organisation for Scientific Research (NWO)VI.Vidi.193.014 Netherlands
CitationJournal: Nat Commun / Year: 2023
Title: Complement is activated by elevated IgG3 hexameric platforms and deposits C4b onto distinct antibody domains.
Authors: Leoni Abendstein / Douwe J Dijkstra / Rayman T N Tjokrodirijo / Peter A van Veelen / Leendert A Trouw / Paul J Hensbergen / Thomas H Sharp /
Abstract: IgG3 is unique among the IgG subclasses due to its extended hinge, allotypic diversity and enhanced effector functions, including highly efficient pathogen neutralisation and complement activation. ...IgG3 is unique among the IgG subclasses due to its extended hinge, allotypic diversity and enhanced effector functions, including highly efficient pathogen neutralisation and complement activation. It is also underrepresented as an immunotherapeutic candidate, partly due to a lack of structural information. Here, we use cryoEM to solve structures of antigen-bound IgG3 alone and in complex with complement components. These structures reveal a propensity for IgG3-Fab clustering, which is possible due to the IgG3-specific flexible upper hinge region and may maximise pathogen neutralisation by forming high-density antibody arrays. IgG3 forms elevated hexameric Fc platforms that extend above the protein corona to maximise binding to receptors and the complement C1 complex, which here adopts a unique protease conformation that may precede C1 activation. Mass spectrometry reveals that C1 deposits C4b directly onto specific IgG3 residues proximal to the Fab domains. Structural analysis shows this to be caused by the height of the C1-IgG3 complex. Together, these data provide structural insights into the role of the unique IgG3 extended hinge, which will aid the development and design of upcoming immunotherapeutics based on IgG3.
History
DepositionNov 28, 2022-
Header (metadata) releaseJun 21, 2023-
Map releaseJun 21, 2023-
UpdateNov 20, 2024-
Current statusNov 20, 2024Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_16227.png

Downloads & links

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Map

FileDownload / File: emd_16227.map.gz / Format: CCP4 / Size: 22.2 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationSubtomogram average of IgG3-Fc hexamer formed on lipid bilayers
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
3.48 Å/pix.
x 180 pix.
= 626.4 Å		3.48 Å/pix.
x 180 pix.
= 626.4 Å		3.48 Å/pix.
x 180 pix.
= 626.4 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 3.48 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 1.25
Minimum - Maximum-1.2636707 - 3.343214
Average (Standard dev.)0.0044321297 (±0.09974515)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions180180180
Spacing180180180
CellA=B=C: 626.4 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_16227_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map of subtomogram average of IgG3-Fc hexamer...

Fileemd_16227_half_map_1.map
AnnotationHalf map of subtomogram average of IgG3-Fc hexamer formed on lipid bilayers
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map of subtomogram average of IgG3-Fc hexamer...

Fileemd_16227_half_map_2.map
AnnotationHalf map of subtomogram average of IgG3-Fc hexamer formed on lipid bilayers
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Fc domain of human IgG3

EntireName: Fc domain of human IgG3
Components
  • Complex: Fc domain of human IgG3
    • Protein or peptide: FLJ00385 protein (Fragment)
    • Protein or peptide: FLJ00385 protein (Fragment)

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Supramolecule #1: Fc domain of human IgG3

SupramoleculeName: Fc domain of human IgG3 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: FLJ00385 protein (Fragment)

MacromoleculeName: FLJ00385 protein (Fragment) / type: protein_or_peptide / ID: 1 / Number of copies: 6 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 23.768957 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: LGGPSVFLFP PKPKDTLMIS RTPEVTCVVV DVSHEDPEVQ FKWYVDGVEV HNAKTKPREE QFNSTFRVVS VLTVLHQDWL NGKEYKCKV SNKALPAPIE KTISKTKGQP REPQVYTLPP SREEMTKNQV SLTCLVKGFY PSDIAVEWES SGQPENNYNT T PPMLDSDG ...String:
LGGPSVFLFP PKPKDTLMIS RTPEVTCVVV DVSHEDPEVQ FKWYVDGVEV HNAKTKPREE QFNSTFRVVS VLTVLHQDWL NGKEYKCKV SNKALPAPIE KTISKTKGQP REPQVYTLPP SREEMTKNQV SLTCLVKGFY PSDIAVEWES SGQPENNYNT T PPMLDSDG SFFLYSKLTV DKSRWQQGNI FSCSVMHEAL HNRFTQKSLS L

UniProtKB: FLJ00385 protein

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Macromolecule #2: FLJ00385 protein (Fragment)

MacromoleculeName: FLJ00385 protein (Fragment) / type: protein_or_peptide / ID: 2 / Number of copies: 6 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 23.782943 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: GPSVFLFPPK PKDTLMISRT PEVTCVVVDV SHEDPEVQFK WYVDGVEVHN AKTKPREEQF NSTFRVVSVL TVLHQDWLNG KEYKCKVSN KALPAPIEKT ISKTKGQPRE PQVYTLPPSR EEMTKNQVSL TCLVKGFYPS DIAVEWESSG QPENNYNTTP P MLDSDGSF ...String:
GPSVFLFPPK PKDTLMISRT PEVTCVVVDV SHEDPEVQFK WYVDGVEVHN AKTKPREEQF NSTFRVVSVL TVLHQDWLNG KEYKCKVSN KALPAPIEKT ISKTKGQPRE PQVYTLPPSR EEMTKNQVSL TCLVKGFYPS DIAVEWESSG QPENNYNTTP P MLDSDGSF FLYSKLTVDK SRWQQGNIFS CSVMHEALHN RFTQKSLSLS P

UniProtKB: FLJ00385 protein

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Experimental details

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Structure determination

Methodcryo EM
Processingsubtomogram averaging
Aggregation stateparticle

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Sample preparation

BufferpH: 7.4 / Details: PBS
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TECNAI ARCTICA
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 1.5 e/Å2
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 6.0 µm / Nominal defocus min: 3.0 µm
Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company

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Image processing

Final reconstructionApplied symmetry - Point group: C6 (6 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 14.0 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: Dynamo / Number subtomograms used: 571
ExtractionNumber tomograms: 60 / Number images used: 1193 / Software - Name: EMAN2
Final 3D classificationSoftware - Name: Dynamo
Final angle assignmentType: ANGULAR RECONSTITUTION / Software - Name: Dynamo
FSC plot (resolution estimation)

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