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- EMDB-42940: Dimer of Hendra virus prefusion F trimers -

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Basic information

Entry
Database: EMDB / ID: EMD-42940
TitleDimer of Hendra virus prefusion F trimers
Map data
Sample
  • Complex: Prefusion-stabilized Hendra virus fusion protein
KeywordsHendra / nipah / henipavirus / Hendra virus / NiV / HeV / fusion / F / antibody / neutralizing / conserved epitope / neutralizing antibody / prefusion / prefusion-stabilized / vaccine / vaccine design / antigen / antigen design / VIRAL PROTEIN
Biological speciesHendra henipavirus
Methodsingle particle reconstruction / cryo EM / Resolution: 4.4 Å
AuthorsByrne PO / Blade EG / McLellan JS
Funding support United States, 1 items
OrganizationGrant numberCountry
Welch FoundationF-0003-19620604 United States
CitationJournal: J Virol / Year: 2024
Title: Prefusion stabilization of the Hendra and Langya virus F proteins.
Authors: Patrick O Byrne / Elizabeth G Blade / Brian E Fisher / David R Ambrozak / Ajit R Ramamohan / Barney S Graham / Rebecca J Loomis / Jason S McLellan /
Abstract: Nipah virus (NiV) and Hendra virus (HeV) are pathogenic paramyxoviruses that cause mild-to-severe disease in humans. As members of the genus, NiV and HeV use an attachment (G) glycoprotein and a ...Nipah virus (NiV) and Hendra virus (HeV) are pathogenic paramyxoviruses that cause mild-to-severe disease in humans. As members of the genus, NiV and HeV use an attachment (G) glycoprotein and a class I fusion (F) glycoprotein to invade host cells. The F protein rearranges from a metastable prefusion form to an extended postfusion form to facilitate host cell entry. Prefusion NiV F elicits higher neutralizing antibody titers than postfusion NiV F, indicating that stabilization of prefusion F may aid vaccine development. A combination of amino acid substitutions (L104C/I114C, L172F, and S191P) is known to stabilize NiV F in its prefusion conformation, although the extent to which substitutions transfer to other henipavirus F proteins is not known. Here, we perform biophysical and structural studies to investigate the mechanism of prefusion stabilization in F proteins from three henipaviruses: NiV, HeV, and Langya virus (LayV). Three known stabilizing substitutions from NiV F transfer to HeV F and exert similar structural and functional effects. One engineered disulfide bond, located near the fusion peptide, is sufficient to stabilize the prefusion conformations of both HeV F and LayV F. Although LayV F shares low overall sequence identity with NiV F and HeV F, the region around the fusion peptide exhibits high sequence conservation across all henipaviruses. Our findings indicate that substitutions targeting this site of conformational change might be applicable to prefusion stabilization of other henipavirus F proteins and support the use of NiV as a prototypical pathogen for henipavirus vaccine antigen design.IMPORTANCEPathogenic henipaviruses such as Nipah virus (NiV) and Hendra virus (HeV) cause respiratory symptoms, with severe cases resulting in encephalitis, seizures, and coma. The work described here shows that the NiV and HeV fusion (F) proteins share common structural features with the F protein from an emerging henipavirus Langya virus (LayV). Sequence alignment alone was sufficient to predict which known prefusion-stabilizing amino acid substitutions from NiV F would stabilize the prefusion conformations of HeV F and LayV F. This work also reveals an unexpected oligomeric interface shared by prefusion HeV F and NiV F. Together, these advances lay a foundation for future antigen design targeting henipavirus F proteins. In this way, Nipah virus can serve as a prototypical pathogen for the development of protective vaccines and monoclonal antibodies to prepare for potential henipavirus outbreaks.
History
DepositionNov 26, 2023-
Header (metadata) releaseDec 27, 2023-
Map releaseDec 27, 2023-
UpdateMar 6, 2024-
Current statusMar 6, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_42940.png

Downloads & links

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Map

FileDownload / File: emd_42940.map.gz / Format: CCP4 / Size: 144.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 0.94 Å
Density
Contour LevelBy AUTHOR: 0.11
Minimum - Maximum-0.09396925 - 0.32993707
Average (Standard dev.)0.00021594521 (±0.014782655)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions336336336
Spacing336336336
CellA=B=C: 315.84 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_42940_half_map_1.map
Projections & Slices
AxesZYX

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Histogram (log scale)

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Half map: #2

Fileemd_42940_half_map_2.map
Projections & Slices
AxesZYX

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Slices (1/2)
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Histogram

Histogram (log scale)

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Sample components

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Entire : Prefusion-stabilized Hendra virus fusion protein

EntireName: Prefusion-stabilized Hendra virus fusion protein
Components
  • Complex: Prefusion-stabilized Hendra virus fusion protein

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Supramolecule #1: Prefusion-stabilized Hendra virus fusion protein

SupramoleculeName: Prefusion-stabilized Hendra virus fusion protein / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Hendra henipavirus

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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

MicroscopeTFS GLACIOS
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 44.0 e/Å2
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.5 µm / Nominal defocus min: 1.5 µm

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Image processing

DetailsPrefusion-stabilized Hendra virus fusion protein. homotrimer
Particle selectionNumber selected: 129200
Startup modelType of model: NONE
Final reconstructionApplied symmetry - Point group: C2 (2 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 4.4 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 7823
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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