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- PDB-8v5a: Prefusion-stabilized Respirovirus type 3 Fusion protein -

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Basic information

Entry
Database: PDB / ID: 8v5a
TitlePrefusion-stabilized Respirovirus type 3 Fusion protein
Components
  • Camelid nanobody 4C06
  • Fusion glycoprotein F0
KeywordsVIRAL PROTEIN/IMMUNE SYSTEM / fusion protein / viral glycoprotein / membrane fusion / VIRAL PROTEIN / VIRAL PROTEIN-IMMUNE SYSTEM complex
Function / homologyPrecursor fusion glycoprotein F0, Paramyxoviridae / Fusion glycoprotein F0 / fusion of virus membrane with host plasma membrane / viral envelope / host cell plasma membrane / virion membrane / plasma membrane / Fusion glycoprotein F0
Function and homology information
Biological speciesHuman respirovirus 3
Lama glama (llama)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3 Å
AuthorsJohnson, N.V. / McLellan, J.S.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Nat Commun / Year: 2024
Title: Universal paramyxovirus vaccine design by stabilizing regions involved in structural transformation of the fusion protein.
Authors: Johannes P M Langedijk / Freek Cox / Nicole V Johnson / Daan van Overveld / Lam Le / Ward van den Hoogen / Richard Voorzaat / Roland Zahn / Leslie van der Fits / Jarek Juraszek / Jason S ...Authors: Johannes P M Langedijk / Freek Cox / Nicole V Johnson / Daan van Overveld / Lam Le / Ward van den Hoogen / Richard Voorzaat / Roland Zahn / Leslie van der Fits / Jarek Juraszek / Jason S McLellan / Mark J G Bakkers /
Abstract: The Paramyxoviridae family encompasses medically significant RNA viruses, including human respiroviruses 1 and 3 (RV1, RV3), and zoonotic pathogens like Nipah virus (NiV). RV3, previously known as ...The Paramyxoviridae family encompasses medically significant RNA viruses, including human respiroviruses 1 and 3 (RV1, RV3), and zoonotic pathogens like Nipah virus (NiV). RV3, previously known as parainfluenza type 3, for which no vaccines or antivirals have been approved, causes respiratory tract infections in vulnerable populations. The RV3 fusion (F) protein is inherently metastable and will likely require prefusion (preF) stabilization for vaccine effectiveness. Here we used structure-based design to stabilize regions involved in structural transformation to generate a preF protein vaccine antigen with high expression and stability, and which, by stabilizing the coiled-coil stem region, does not require a heterologous trimerization domain. The preF candidate induces strong neutralizing antibody responses in both female naïve and pre-exposed mice and provides protection in a cotton rat challenge model (female). Despite the evolutionary distance of paramyxovirus F proteins, their structural transformation and local regions of instability are conserved, which allows successful transfer of stabilizing substitutions to the distant preF proteins of RV1 and NiV. This work presents a successful vaccine antigen design for RV3 and provides a toolbox for future paramyxovirus vaccine design and pandemic preparedness.
History
DepositionNov 30, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 19, 2024Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Fusion glycoprotein F0
Y: Camelid nanobody 4C06
B: Fusion glycoprotein F0
W: Camelid nanobody 4C06
C: Fusion glycoprotein F0
U: Camelid nanobody 4C06


Theoretical massNumber of molelcules
Total (without water)199,9076
Polymers199,9076
Non-polymers00
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: 54147.891 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Human respirovirus 3 / Cell line (production host): Expi293F / Production host: Homo sapiens (human) / References: UniProt: A0A023PFZ0
#2: Antibody Camelid nanobody 4C06


Mass: 12487.816 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Lama glama (llama) / Production host: Escherichia coli (E. coli)

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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: Trimeric Human Respirovirus 3 Fusion Protein bound to 3 copies of nanobody 4C06
Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Molecular weightValue: 0.2325 MDa / Experimental value: NO
Source (natural)Organism: Human respirovirus 3
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 8
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: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 3000 nm / Nominal defocus min: 1000 nm
Image recordingElectron dose: 70 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM softwareName: PHENIX / Version: 1.18.2_3874: / Category: model refinement
CTF correctionType: NONE
3D reconstructionResolution: 3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 193265 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00913248
ELECTRON MICROSCOPYf_angle_d1.04317967
ELECTRON MICROSCOPYf_dihedral_angle_d36.5671824
ELECTRON MICROSCOPYf_chiral_restr0.0642136
ELECTRON MICROSCOPYf_plane_restr0.0072307

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