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- EMDB-22334: Human parainfluenza virus fusion complex glycoproteins imaged in ... -

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Basic information

Entry
Database: EMDB / ID: EMD-22334
TitleHuman parainfluenza virus fusion complex glycoproteins imaged in action on authentic viral surfaces: Subtomogram average of hemagglutinin-neuraminidase (HN) and fusion (F) protein complex prior to receptor engagement
Map dataCryo-electron tomography and subtomogram averaging of the HN and F complex on the surface of HPIV3
Sample
  • Virus: Human respirovirus 3
Biological speciesHuman respirovirus 3
Methodsubtomogram averaging / cryo EM / Resolution: 17.18 Å
AuthorsMarcink TC / des Georges A / Porotto M / Moscona A
Funding support United States, 4 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)RO1AI031971 United States
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)RO1AI121349 United States
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)RO1AI114736 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35GM133598 United States
CitationJournal: mBio / Year: 2020
Title: Hijacking the Fusion Complex of Human Parainfluenza Virus as an Antiviral Strategy.
Authors: T C Marcink / E Yariv / K Rybkina / V Más / F T Bovier / A des Georges / A L Greninger / C A Alabi / M Porotto / N Ben-Tal / A Moscona /
Abstract: The receptor binding protein of parainfluenza virus, hemagglutinin-neuraminidase (HN), is responsible for actively triggering the viral fusion protein (F) to undergo a conformational change leading ...The receptor binding protein of parainfluenza virus, hemagglutinin-neuraminidase (HN), is responsible for actively triggering the viral fusion protein (F) to undergo a conformational change leading to insertion into the target cell and fusion of the virus with the target cell membrane. For proper viral entry to occur, this process must occur when HN is engaged with host cell receptors at the cell surface. It is possible to interfere with this process through premature activation of the F protein, distant from the target cell receptor. Conformational changes in the F protein and adoption of the postfusion form of the protein prior to receptor engagement of HN at the host cell membrane inactivate the virus. We previously identified small molecules that interact with HN and induce it to activate F in an untimely fashion, validating a new antiviral strategy. To obtain highly active pretriggering candidate molecules we carried out a virtual modeling screen for molecules that interact with sialic acid binding site II on HN, which we propose to be the site responsible for activating F. To directly assess the mechanism of action of one such highly effective new premature activating compound, PAC-3066, we use cryo-electron tomography on authentic intact viral particles for the first time to examine the effects of PAC-3066 treatment on the conformation of the viral F protein. We present the first direct observation of the conformational rearrangement induced in the viral F protein. Paramyxoviruses, including human parainfluenza virus type 3, are internalized into host cells by fusion between viral and target cell membranes. The receptor binding protein, hemagglutinin-neuraminidase (HN), upon binding to its cell receptor, triggers conformational changes in the fusion protein (F). This action of HN activates F to reach its fusion-competent state. Using small molecules that interact with HN, we can induce the premature activation of F and inactivate the virus. To obtain highly active pretriggering compounds, we carried out a virtual modeling screen for molecules that interact with a sialic acid binding site on HN that we propose to be the site involved in activating F. We use cryo-electron tomography of authentic intact viral particles for the first time to directly assess the mechanism of action of this treatment on the conformation of the viral F protein and present the first direct observation of the induced conformational rearrangement in the viral F protein.
History
DepositionJul 20, 2020-
Header (metadata) releaseSep 16, 2020-
Map releaseSep 16, 2020-
UpdateSep 16, 2020-
Current statusSep 16, 2020Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 1.4
  • Imaged by UCSF Chimera
  • Download
  • Surface view colored by height
  • Surface level: 1.4
  • Imaged by UCSF Chimera
  • Download
Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_22334.png

Downloads & links

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Map

FileDownload / File: emd_22334.map.gz / Format: CCP4 / Size: 2.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationCryo-electron tomography and subtomogram averaging of the HN and F complex on the surface of HPIV3
Voxel sizeX=Y=Z: 3.68 Å
Density
Contour LevelBy AUTHOR: 1.4 / Movie #1: 1.4
Minimum - Maximum-4.533323 - 7.232372
Average (Standard dev.)-0.16588095 (±0.87065214)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions888888
Spacing888888
CellA=B=C: 323.84 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z3.683.683.68
M x/y/z888888
origin x/y/z0.0000.0000.000
length x/y/z323.840323.840323.840
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS888888
D min/max/mean-4.5337.232-0.166

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Supplemental data

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Sample components

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Entire : Human respirovirus 3

EntireName: Human respirovirus 3
Components
  • Virus: Human respirovirus 3

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Supramolecule #1: Human respirovirus 3

SupramoleculeName: Human respirovirus 3 / type: virus / ID: 1 / Parent: 0 / NCBI-ID: 11216 / Sci species name: Human respirovirus 3 / Virus type: VIRION / Virus isolate: STRAIN / Virus enveloped: Yes / Virus empty: No
Host (natural)Organism: Homo sapiens (human)
Host systemOrganism: Chlorocebus sabaeus (green monkey)

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Experimental details

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Structure determination

Methodcryo EM
Processingsubtomogram averaging
Aggregation stateparticle

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Sample preparation

BufferpH: 7.4
GridModel: PELCO Ultrathin Carbon with Lacey Carbon / Material: GOLD / Mesh: 300 / Support film - Material: CARBON / Support film - Film thickness: 3.0 nm / Pretreatment - Type: PLASMA CLEANING / Pretreatment - Atmosphere: OTHER
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277.15 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Digitization - Dimensions - Width: 5760 pixel / Digitization - Dimensions - Height: 4092 pixel / Digitization - Sampling interval: 5.0 µm / Average exposure time: 0.4 sec. / Average electron dose: 3.42 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD
Sample stageSpecimen holder model: GATAN 626 SINGLE TILT LIQUID NITROGEN CRYO TRANSFER HOLDER
Cooling holder cryogen: NITROGEN

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Image processing

Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 17.18 Å / Resolution method: FSC 0.5 CUT-OFF / Software - Name: Dynamo (ver. 1.1.509) / Number subtomograms used: 1096
ExtractionNumber tomograms: 2 / Number images used: 5153 / Software - Name: Dynamo (ver. 1.1.509)
CTF correctionSoftware - Name: Appion (ver. 1.2.2)
Final angle assignmentType: ANGULAR RECONSTITUTION / Software - Name: Dynamo (ver. 1.1.509)
FSC plot (resolution estimation)

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Atomic model buiding 1

RefinementProtocol: RIGID BODY FIT

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