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- EMDB-44117: Cryo-EM structure of Prefusion RSV F (RSV220975) -

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Basic information

Entry
Database: EMDB / ID: EMD-44117
TitleCryo-EM structure of Prefusion RSV F (RSV220975)
Map data
Sample
  • Complex: Prefusion RSV F (RSV220975)
    • Protein or peptide: Fusion glycoprotein F0
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
KeywordsPrefusion / RSV / Cryo-EM / VIRUS / VIRAL PROTEIN
Function / homology
Function and homology information


symbiont-mediated induction of syncytium formation / host cell Golgi membrane / entry receptor-mediated virion attachment to host cell / fusion of virus membrane with host plasma membrane / viral envelope / symbiont entry into host cell / host cell plasma membrane / virion membrane / membrane
Similarity search - Function
Precursor fusion glycoprotein F0, Paramyxoviridae / Fusion glycoprotein F0
Similarity search - Domain/homology
Fusion glycoprotein F0
Similarity search - Component
Biological speciesHuman metapneumovirus / Human orthopneumovirus
Methodsingle particle reconstruction / cryo EM / Resolution: 3.28 Å
AuthorsYu X / Langedijk JPM
Funding support1 items
OrganizationGrant numberCountry
Not funded
CitationJournal: Nat Microbiol / Year: 2024
Title: A foldon-free prefusion F trimer vaccine for respiratory syncytial virus to reduce off-target immune responses.
Authors: Mark J G Bakkers / Freek Cox / Annemart Koornneef / Xiaodi Yu / Daan van Overveld / Lam Le / Ward van den Hoogen / Joost Vaneman / Anne Thoma / Richard Voorzaat / Lisanne Tettero / Jarek ...Authors: Mark J G Bakkers / Freek Cox / Annemart Koornneef / Xiaodi Yu / Daan van Overveld / Lam Le / Ward van den Hoogen / Joost Vaneman / Anne Thoma / Richard Voorzaat / Lisanne Tettero / Jarek Juraszek / Leslie van der Fits / Roland Zahn / Johannes P M Langedijk /
Abstract: Respiratory syncytial virus (RSV) is a major cause of severe respiratory disease in infants and older people. Current RSV subunit vaccines are based on a fusion protein that is stabilized in the ...Respiratory syncytial virus (RSV) is a major cause of severe respiratory disease in infants and older people. Current RSV subunit vaccines are based on a fusion protein that is stabilized in the prefusion conformation and linked to a heterologous foldon trimerization domain to obtain a prefusion F (preF) trimer. Here we show that current RSV vaccines induce undesirable anti-foldon antibodies in non-human primates, mice and humans. To overcome this, we designed a foldon-free RSV preF trimer by elucidating the structural basis of trimerization-induced preF destabilization through molecular dynamics simulations and by introducing amino acid substitutions that negate hotspots of charge repulsion. The highly stable prefusion conformation was validated using antigenic and cryo-electron microscopy analysis. The preF is immunogenic and protective in naive mouse models and boosts neutralizing antibody titres in RSV-pre-exposed mice and non-human primates, while achieving similar titres to approved RSV vaccines in mice. This stable preF design is a promising option as a foldon-independent candidate for a next-generation RSV vaccine immunogen.
History
DepositionMar 17, 2024-
Header (metadata) releaseOct 16, 2024-
Map releaseOct 16, 2024-
UpdateDec 11, 2024-
Current statusDec 11, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_44117.png

Downloads & links

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Map

FileDownload / File: emd_44117.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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Contrast
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AxesZ (Sec.)Y (Row.)X (Col.)
0.91 Å/pix.
x 320 pix.
= 291.2 Å		0.91 Å/pix.
x 320 pix.
= 291.2 Å		0.91 Å/pix.
x 320 pix.
= 291.2 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.91 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.1
Minimum - Maximum-1.8733807 - 2.3603287
Average (Standard dev.)0.0006473416 (±0.046317674)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 291.2 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_44117_half_map_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_44117_half_map_2.map
Projections & Slices
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Histogram (log scale)

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Sample components

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Entire : Prefusion RSV F (RSV220975)

EntireName: Prefusion RSV F (RSV220975)
Components
  • Complex: Prefusion RSV F (RSV220975)
    • Protein or peptide: Fusion glycoprotein F0
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: Prefusion RSV F (RSV220975)

SupramoleculeName: Prefusion RSV F (RSV220975) / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Human metapneumovirus

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Macromolecule #1: Fusion glycoprotein F0

MacromoleculeName: Fusion glycoprotein F0 / type: protein_or_peptide / ID: 1 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Human orthopneumovirus
Molecular weightTheoretical: 58.299879 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MELLILKANA ITTILTAVTF CFASGQNITE EFYQSTCSAV SKGYLSALRT GWYTSVITIE LSNIKENKCN GTDAKVKLIK QELDKYKNA VTELQLLMQS TQATNNRARR ELPRFMNYTL NNAKKTNVTL SKKRKRRFLG FLLGVGSAIA SGVAVSKVLH L EGEVNKIK ...String:
MELLILKANA ITTILTAVTF CFASGQNITE EFYQSTCSAV SKGYLSALRT GWYTSVITIE LSNIKENKCN GTDAKVKLIK QELDKYKNA VTELQLLMQS TQATNNRARR ELPRFMNYTL NNAKKTNVTL SKKRKRRFLG FLLGVGSAIA SGVAVSKVLH L EGEVNKIK SALLSTNKAV VSLSNGVSVL TSKVLDLKNY IDKQLLPIVN KQSCSIPNIE TVIEFQQKNN RLLEITREFS VN AGVTTPV STYMLTNSEL LSLINDMPIT NDQKKLMSNN VQIVRQQSYS IMSIIKEEVL AYVVQLPLYG VIDTPCWKLH TSP LCTTNT KEGSNICLTR TDRGWYCDNA GSVSFFPLAE TCKVQSNRVF CDTMNSLTLP SEVNLCNVDI FNPKYDCKIM TSKT DVSSS VITSLGAIVS CYGKTKCTAS NKNRGIIKTF SNGCDYVSNK GVDTVSVGNT LYYVNKQEGK SLYVKGEPII NFYDP LVFP SNLFYASISQ VNEKINQSLA WIRKFDELLH NVNAVKSTIN

UniProtKB: Fusion glycoprotein F0

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Macromolecule #2: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 2 / Number of copies: 6 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

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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 TALOS ARCTICA
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 40.0 e/Å2
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.4 µm / Nominal defocus min: 1.2 µm
Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company

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Image processing

Startup modelType of model: INSILICO MODEL
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.28 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 282698
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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