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- EMDB-16250: Subtomogram average of a complex of IgG3-C1-C4b after focussed re... -

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Basic information

Entry
Database: EMDB / ID: EMD-16250
TitleSubtomogram average of a complex of IgG3-C1-C4b after focussed refinement around the C4b region
Map dataSubtomogram average of a complex of IgG3-C1-C4b after focussed refinement around the C4b region
Sample
  • Complex: Complex of IgG3-C1-C4b after focussed refinement around the C4b region
KeywordsIgG3 / antibody / complement / C1 / C4b / IMMUNE SYSTEM
Biological speciesHomo sapiens (human)
Methodsubtomogram averaging / cryo EM / Resolution: 30.0 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
DepositionDec 1, 2022-
Header (metadata) releaseJun 21, 2023-
Map releaseJun 21, 2023-
UpdateJul 19, 2023-
Current statusJul 19, 2023Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_16250.png

Downloads & links

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Map

FileDownload / File: emd_16250.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationSubtomogram average of a complex of IgG3-C1-C4b after focussed refinement around the C4b region
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
3.48 Å/pix.
x 256 pix.
= 890.88 Å		3.48 Å/pix.
x 256 pix.
= 890.88 Å		3.48 Å/pix.
x 256 pix.
= 890.88 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: 0.25
Minimum - Maximum-1.6619129 - 3.915446
Average (Standard dev.)0.0054292004 (±0.07718664)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 890.88 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_16250_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 a subtomogram average of a...

Fileemd_16250_half_map_1.map
AnnotationHalf map of a subtomogram average of a complex of IgG3-C1-C4b after focussed refinement around the C4b region
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map of a subtomogram average of a...

Fileemd_16250_half_map_2.map
AnnotationHalf map of a subtomogram average of a complex of IgG3-C1-C4b after focussed refinement around the C4b region
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Complex of IgG3-C1-C4b after focussed refinement around the C4b region

EntireName: Complex of IgG3-C1-C4b after focussed refinement around the C4b region
Components
  • Complex: Complex of IgG3-C1-C4b after focussed refinement around the C4b region

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Supramolecule #1: Complex of IgG3-C1-C4b after focussed refinement around the C4b region

SupramoleculeName: Complex of IgG3-C1-C4b after focussed refinement around the C4b region
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)

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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 / Nominal magnification: 49000
Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company

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Image processing

Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 30.0 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: Dynamo / Number subtomograms used: 2428
ExtractionNumber tomograms: 104 / Number images used: 2561 / Method: Particles picked manually / Software - Name: EMAN2
Final 3D classificationSoftware - Name: Dynamo
Final angle assignmentType: ANGULAR RECONSTITUTION / Software - Name: Dynamo
FSC plot (resolution estimation)

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