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- EMDB-40306: BtCoV-422 spike in complex with JC57-11 Fab, global map -

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Basic information

Entry
Database: EMDB / ID: EMD-40306
TitleBtCoV-422 spike in complex with JC57-11 Fab, global map
Map dataBtCoV-422 spike JC57-11 Fab global sharpened map
Sample
  • Complex: BtCoV-422 spike in complex with JC57-11 Fab
    • Complex: BtCoV-422 spike
    • Complex: JC57-11 Fab
Keywordscoronavirus / MERS / neutralizing / antibody / MERS-like / merbecovirus / bat / virus / CDRH3 / RBD / VIRAL PROTEIN
Biological speciesMiddle East respiratory syndrome-related coronavirus / Macaca (macaques)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.0 Å
AuthorsMcFadden E / McLellan JS
Funding support United States, 1 items
OrganizationGrant numberCountry
Bill & Melinda Gates Foundation26-7535-3450 United States
CitationJournal: Sci Transl Med / Year: 2023
Title: A MERS-CoV antibody neutralizes a pre-emerging group 2c bat coronavirus.
Authors: Longping V Tse / Yixuan J Hou / Elizabeth McFadden / Rhianna E Lee / Trevor D Scobey / Sarah R Leist / David R Martinez / Rita M Meganck / Alexandra Schäfer / Boyd L Yount / Teresa Mascenik ...Authors: Longping V Tse / Yixuan J Hou / Elizabeth McFadden / Rhianna E Lee / Trevor D Scobey / Sarah R Leist / David R Martinez / Rita M Meganck / Alexandra Schäfer / Boyd L Yount / Teresa Mascenik / John M Powers / Scott H Randell / Yi Zhang / Lingshu Wang / John Mascola / Jason S McLellan / Ralph S Baric /
Abstract: The repeated emergence of zoonotic human betacoronaviruses (β-CoVs) dictates the need for broad therapeutics and conserved epitope targets for countermeasure design. Middle East respiratory syndrome ...The repeated emergence of zoonotic human betacoronaviruses (β-CoVs) dictates the need for broad therapeutics and conserved epitope targets for countermeasure design. Middle East respiratory syndrome (MERS)-related coronaviruses (CoVs) remain a pressing concern for global health preparedness. Using metagenomic sequence data and CoV reverse genetics, we recovered a full-length wild-type MERS-like BtCoV//GD/2014-422 (BtCoV-422) recombinant virus, as well as two reporter viruses, and evaluated their human emergence potential and susceptibility to currently available countermeasures. Similar to MERS-CoV, BtCoV-422 efficiently used human and other mammalian dipeptidyl peptidase protein 4 (DPP4) proteins as entry receptors and an alternative DPP4-independent infection route in the presence of exogenous proteases. BtCoV-422 also replicated efficiently in primary human airway, lung endothelial, and fibroblast cells, although less efficiently than MERS-CoV. However, BtCoV-422 shows minor signs of infection in 288/330 human DPP4 transgenic mice. Several broad CoV antivirals, including nucleoside analogs and 3C-like/M protease inhibitors, demonstrated potent inhibition against BtCoV-422 in vitro. Serum from mice that received a MERS-CoV mRNA vaccine showed reduced neutralizing activity against BtCoV-422. Although most MERS-CoV-neutralizing monoclonal antibodies (mAbs) had limited activity, one anti-MERS receptor binding domain mAb, JC57-11, neutralized BtCoV-422 potently. A cryo-electron microscopy structure of JC57-11 in complex with BtCoV-422 spike protein revealed the mechanism of cross-neutralization involving occlusion of the DPP4 binding site, highlighting its potential as a broadly neutralizing mAb for group 2c CoVs that use DPP4 as a receptor. These studies provide critical insights into MERS-like CoVs and provide candidates for countermeasure development.
History
DepositionApr 3, 2023-
Header (metadata) releaseOct 4, 2023-
Map releaseOct 4, 2023-
UpdateOct 4, 2023-
Current statusOct 4, 2023Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

Downloads & links

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Map

FileDownload / File: emd_40306.map.gz / Format: CCP4 / Size: 244.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationBtCoV-422 spike JC57-11 Fab global sharpened map
Voxel sizeX=Y=Z: 0.8332 Å
Density
Contour LevelBy AUTHOR: 0.15
Minimum - Maximum-0.7458022 - 1.213159
Average (Standard dev.)0.0011354783 (±0.036426384)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions400400400
Spacing400400400
CellA=B=C: 333.28 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: BtCoV-422 spike JC57-11 Fab global map run through...

Fileemd_40306_additional_1.map
AnnotationBtCoV-422 spike JC57-11 Fab global map run through DeepEMhancer, used for generation of the composite map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

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Additional map: BtCoV-422 spike JC57-11 Fab global unsharpened map

Fileemd_40306_additional_2.map
AnnotationBtCoV-422 spike JC57-11 Fab global unsharpened map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

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Half map: BtCoV-422 spike JC57-11 Fab global half map A

Fileemd_40306_half_map_1.map
AnnotationBtCoV-422 spike JC57-11 Fab global half map A
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

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Half map: BtCoV-422 spike JC57-11 Fab global half map B

Fileemd_40306_half_map_2.map
AnnotationBtCoV-422 spike JC57-11 Fab global half map B
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

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Sample components

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Entire : BtCoV-422 spike in complex with JC57-11 Fab

EntireName: BtCoV-422 spike in complex with JC57-11 Fab
Components
  • Complex: BtCoV-422 spike in complex with JC57-11 Fab
    • Complex: BtCoV-422 spike
    • Complex: JC57-11 Fab

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Supramolecule #1: BtCoV-422 spike in complex with JC57-11 Fab

SupramoleculeName: BtCoV-422 spike in complex with JC57-11 Fab / type: complex / ID: 1 / Parent: 0
Molecular weightTheoretical: 650 KDa

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Supramolecule #2: BtCoV-422 spike

SupramoleculeName: BtCoV-422 spike / type: complex / ID: 2 / Parent: 1
Source (natural)Organism: Middle East respiratory syndrome-related coronavirus
Molecular weightTheoretical: 600 KDa

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Supramolecule #3: JC57-11 Fab

SupramoleculeName: JC57-11 Fab / type: complex / ID: 3 / Parent: 1
Source (natural)Organism: Macaca (macaques)
Molecular weightTheoretical: 50 KDa

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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

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: OTHER / Imaging mode: DIFFRACTION / Nominal defocus max: 2.5 µm / Nominal defocus min: 1.5 µm
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 80.5 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 139177
Startup modelType of model: NONE
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.0 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 57821
FSC plot (resolution estimation)

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