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- PDB-9b2x: Cryo-EM structure of Prefusion RSV F (RSV220975) -

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Basic information

Entry
Database: PDB / ID: 9b2x
TitleCryo-EM structure of Prefusion RSV F (RSV220975)
ComponentsFusion glycoprotein F0
KeywordsVIRAL PROTEIN / Prefusion / RSV / Cryo-EM / VIRUS
Function / homology
Function and homology information


symbiont-mediated induction of syncytium formation / host cell Golgi membrane / entry receptor-mediated virion attachment to host cell / symbiont entry into host cell / fusion of virus membrane with host plasma membrane / viral envelope / 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 orthopneumovirus
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.28 Å
AuthorsYu, X. / Langedijk, J.P.M.
Funding support1items
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, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 16, 2024Provider: repository / Type: Initial release
Revision 1.1Nov 6, 2024Group: Data collection / Category: em_admin / Item: _em_admin.last_update
Revision 1.2Dec 4, 2024Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID / _citation_author.name / _em_admin.last_update
Revision 1.3Dec 11, 2024Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Fusion glycoprotein F0
B: Fusion glycoprotein F0
C: Fusion glycoprotein F0
hetero molecules


Theoretical massNumber of molelcules
Total (without water)176,2279
Polymers174,9003
Non-polymers1,3276
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Fusion glycoprotein F0


Mass: 58299.879 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Human orthopneumovirus / Gene: F, MZ07_64039gpF, MZ07_64040gpF / Production host: Homo sapiens (human) / References: UniProt: A0A1P8J9V4
#2: Sugar
ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0
Has ligand of interestN
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Prefusion RSV F (RSV220975) / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Human metapneumovirus
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company
MicroscopyModel: FEI TALOS ARCTICA
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2400 nm / Nominal defocus min: 1200 nm
Image recordingElectron dose: 40 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.28 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 282698 / Symmetry type: POINT

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