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- EMDB-41716: Monomeric Lassa glycoprotein bound to 25.10C Fab and two interior... -

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Entry
Database: EMDB / ID: EMD-41716
TitleMonomeric Lassa glycoprotein bound to 25.10C Fab and two interior-binding rabbit polyclonal Fabs
Map data
Sample
  • Complex: Monomeric Lassa GPC bound to 25.10C Fab and two polyclonal rabbit Fabs
KeywordsLassa virus glycoprotein complex / GPC / immune complex / antibody / polyclonal antibody / base antibody / VIRAL PROTEIN / VIRAL PROTEIN-IMMUNE SYSTEM complex
Biological speciesLassa virus
Methodsingle particle reconstruction / cryo EM / Resolution: 8.1 Å
AuthorsBrouwer PJM / Perrett HR / Ward AB
Funding support United States, Netherlands, 4 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)1F31Al172358 United States
Netherlands Organisation for Scientific Research (NWO)Rubicon Fellowship Netherlands
Bill & Melinda Gates FoundationINV-004923 United States
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)AI71438 United States
CitationJournal: Cell Rep / Year: 2024
Title: Defining bottlenecks and opportunities for Lassa virus neutralization by structural profiling of vaccine-induced polyclonal antibody responses.
Authors: Philip J M Brouwer / Hailee R Perrett / Tim Beaumont / Haye Nijhuis / Sabine Kruijer / Judith A Burger / Ilja Bontjer / Wen-Hsin Lee / James A Ferguson / Martin Schauflinger / Helena Müller- ...Authors: Philip J M Brouwer / Hailee R Perrett / Tim Beaumont / Haye Nijhuis / Sabine Kruijer / Judith A Burger / Ilja Bontjer / Wen-Hsin Lee / James A Ferguson / Martin Schauflinger / Helena Müller-Kräuter / Rogier W Sanders / Thomas Strecker / Marit J van Gils / Andrew B Ward /
Abstract: Lassa fever continues to be a major public health burden in West Africa, yet effective therapies or vaccines are lacking. The isolation of protective neutralizing antibodies against the Lassa virus ...Lassa fever continues to be a major public health burden in West Africa, yet effective therapies or vaccines are lacking. The isolation of protective neutralizing antibodies against the Lassa virus glycoprotein complex (GPC) justifies the development of vaccines that can elicit strong neutralizing antibody responses. However, Lassa vaccine candidates have generally been unsuccessful at doing so, and the associated antibody responses to these vaccines remain poorly characterized. Here, we establish an electron microscopy-based epitope mapping workflow that enables high-resolution structural characterization of polyclonal antibodies to the GPC. By applying this method to rabbits vaccinated with a recombinant GPC vaccine and a GPC-derived virus-like particle, we reveal determinants of neutralization that involve epitopes of the GPC-A competition cluster. Furthermore, by identifying undescribed immunogenic off-target epitopes, we expose the challenges that recombinant GPC vaccines face. By enabling detailed polyclonal antibody characterization, our work ushers in a next generation of more rational Lassa vaccine design.
History
DepositionAug 25, 2023-
Header (metadata) releaseNov 13, 2024-
Map releaseNov 13, 2024-
UpdateNov 13, 2024-
Current statusNov 13, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_41716.png

Downloads & links

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Map

FileDownload / File: emd_41716.map.gz / Format: CCP4 / Size: 600.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
0.73 Å/pix.
x 540 pix.
= 391.5 Å		0.73 Å/pix.
x 540 pix.
= 391.5 Å		0.73 Å/pix.
x 540 pix.
= 391.5 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.725 Å
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Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.103
Minimum - Maximum-0.25181463 - 0.40273988
Average (Standard dev.)0.000056553607 (±0.0075163343)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions540540540
Spacing540540540
CellA=B=C: 391.5 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_41716_msk_1.map
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Half map: #1

Fileemd_41716_half_map_1.map
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Half map: #2

Fileemd_41716_half_map_2.map
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Sample components

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Entire : Monomeric Lassa GPC bound to 25.10C Fab and two polyclonal rabbit Fabs

EntireName: Monomeric Lassa GPC bound to 25.10C Fab and two polyclonal rabbit Fabs
Components
  • Complex: Monomeric Lassa GPC bound to 25.10C Fab and two polyclonal rabbit Fabs

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Supramolecule #1: Monomeric Lassa GPC bound to 25.10C Fab and two polyclonal rabbit Fabs

SupramoleculeName: Monomeric Lassa GPC bound to 25.10C Fab and two polyclonal rabbit Fabs
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#8
Source (natural)Organism: Lassa virus / Strain: Mouse/Sierra Leone/Josiah/1976

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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

Concentration0.1 mg/mL
BufferpH: 7.4
GridModel: Quantifoil R1.2/1.3 / Material: GRAPHENE OXIDE / Mesh: 400
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS GLACIOS
Image recordingFilm or detector model: TFS FALCON 4i (4k x 4k) / Average electron dose: 49.5 e/Å2
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 70.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 1.4000000000000001 µm / Nominal defocus min: 0.8 µm
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER

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Image processing

Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

8ejd

Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 8.1 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 20839
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
FSC plot (resolution estimation)

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