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- EMDB-11594: The structure of HAdV-D56 in complex with CD46 -

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Basic information

Entry
Database: EMDB / ID: EMD-11594
TitleThe structure of HAdV-D56 in complex with CD46
Map dataFull unmasked map
Sample
  • Virus: Human adenovirus 56
    • Complex: CD46 complement regulatory protein
Biological speciesHomo sapiens (human) / Human adenovirus 56
Methodsingle particle reconstruction / cryo EM / Resolution: 5.11 Å
AuthorsRafie K / Carlson L-A
Funding supportEuropean Union, Sweden, 4 items
OrganizationGrant numberCountry
Human Frontier Science Program (HFSP)CDA00047/2017-CEuropean Union
Swedish Research CouncilDnr 2019-01472 Sweden
Knut and Alice Wallenberg Foundation Sweden
Swedish Research Council2017-508 00859 Sweden
CitationJournal: Proc Natl Acad Sci U S A / Year: 2021
Title: Human species D adenovirus hexon capsid protein mediates cell entry through a direct interaction with CD46.
Authors: B David Persson / Lijo John / Karim Rafie / Michael Strebl / Lars Frängsmyr / Monika Z Ballmann / Katja Mindler / Menzo Havenga / Angelique Lemckert / Thilo Stehle / Lars-Anders Carlson / Niklas Arnberg /
Abstract: Human adenovirus species D (HAdV-D) types are currently being explored as vaccine vectors for coronavirus disease 2019 (COVID-19) and other severe infectious diseases. The efficacy of such vector- ...Human adenovirus species D (HAdV-D) types are currently being explored as vaccine vectors for coronavirus disease 2019 (COVID-19) and other severe infectious diseases. The efficacy of such vector-based vaccines depends on functional interactions with receptors on host cells. Adenoviruses of different species are assumed to enter host cells mainly by interactions between the knob domain of the protruding fiber capsid protein and cellular receptors. Using a cell-based receptor-screening assay, we identified CD46 as a receptor for HAdV-D56. The function of CD46 was validated in infection experiments using cells lacking and overexpressing CD46, and by competition infection experiments using soluble CD46. Remarkably, unlike HAdV-B types that engage CD46 through interactions with the knob domain of the fiber protein, HAdV-D types infect host cells through a direct interaction between CD46 and the hexon protein. Soluble hexon proteins (but not fiber knob) inhibited HAdV-D56 infection, and surface plasmon analyses demonstrated that CD46 binds to HAdV-D hexon (but not fiber knob) proteins. Cryoelectron microscopy analysis of the HAdV-D56 virion-CD46 complex confirmed the interaction and showed that CD46 binds to the central cavity of hexon trimers. Finally, soluble CD46 inhibited infection by 16 out of 17 investigated HAdV-D types, suggesting that CD46 is an important receptor for a large group of adenoviruses. In conclusion, this study identifies a noncanonical entry mechanism used by human adenoviruses, which adds to the knowledge of adenovirus biology and can also be useful for development of adenovirus-based vaccine vectors.
History
DepositionAug 6, 2020-
Header (metadata) releaseJan 13, 2021-
Map releaseJan 13, 2021-
UpdateJan 13, 2021-
Current statusJan 13, 2021Processing site: PDBe / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.0035
  • Imaged by UCSF Chimera
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  • Surface view colored by radius
  • Surface level: 0.0035
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_11594.png

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Map

FileDownload / File: emd_11594.map.gz / Format: CCP4 / Size: 6.9 GB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationFull unmasked map
Voxel sizeX=Y=Z: 1.042 Å
Density
Contour LevelBy AUTHOR: 0.0035 / Movie #1: 0.0035
Minimum - Maximum-0.0071373945 - 0.014046683
Average (Standard dev.)0.00047397806 (±0.0009779861)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions123012301230
Spacing123012301230
CellA=B=C: 1281.66 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.0421.0421.042
M x/y/z123012301230
origin x/y/z0.0000.0000.000
length x/y/z1281.6601281.6601281.660
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ540540540
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS123012301230
D min/max/mean-0.0070.0140.000

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Supplemental data

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Half map: Half map 2

Fileemd_11594_half_map_1.map
AnnotationHalf map 2
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map 1

Fileemd_11594_half_map_2.map
AnnotationHalf map 1
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Human adenovirus 56

EntireName: Human adenovirus 56
Components
  • Virus: Human adenovirus 56
    • Complex: CD46 complement regulatory protein

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Supramolecule #1: Human adenovirus 56

SupramoleculeName: Human adenovirus 56 / type: virus / ID: 1 / Parent: 0 / NCBI-ID: 880565 / Sci species name: Human adenovirus 56 / Virus type: VIRION / Virus isolate: SEROTYPE / Virus enveloped: No / Virus empty: No
Host (natural)Organism: Homo sapiens (human)
Virus shellShell ID: 1 / Name: Human Adenovirus Serotype D 56 / Diameter: 1000.0 Å

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Supramolecule #2: CD46 complement regulatory protein

SupramoleculeName: CD46 complement regulatory protein / type: complex / ID: 2 / Parent: 1
Details: reombinantely expressed CD46 purchased from Sino Biological Inc (Cat#: 12239-H08H).
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Homo sapiens (human) / Recombinant cell: HEK293
Molecular weightExperimental: 60 KDa

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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

Concentration3.6 mg/mL
BufferpH: 7.4
Details: Commercial PBS buffer stock. Medicargo, PBS tablets, 09-9400-100
GridModel: Quantifoil R2/2 / Material: COPPER / Mesh: 200 / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Atmosphere: OTHER / Pretreatment - Pressure: 0.037 kPa
VitrificationCryogen name: ETHANE / Chamber humidity: 80 % / Chamber temperature: 295.15 K / Instrument: FEI VITROBOT MARK IV
Details60 uL of HadV-D56 at 1.2 mg/mL was combined with 60 uL of a 0.5 mg/mL solution of recombinant CD46, incubated on ice for 15 minutes. The sample was subsequently concentrated to a final volum of 20 uL with a nominal concentration of 3.6 and 1.5 mg/mL for HAdV-D56 and CD46, respectively.

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 70.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: -0.003 µm / Nominal defocus min: -0.0008 µm / Nominal magnification: 130000
Specialist opticsEnergy filter - Name: GIF Bioquantum / Energy filter - Slit width: 20 eV
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: COUNTING / Digitization - Frames/image: 2-20 / Average exposure time: 4.5 sec. / Average electron dose: 0.94 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 1317 / Details: Manually picked
CTF correctionSoftware - Name: Gctf (ver. 1.06)
Startup modelType of model: OTHER
Details: Map submitted to EMDB for a different publication EMD-ID will be supplied as soon as accepted.
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 3.1)
Final 3D classificationNumber classes: 2 / Software - Name: RELION (ver. 3.1)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 3.1)
Final reconstructionNumber classes used: 1 / Resolution.type: BY AUTHOR / Resolution: 5.11 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 3.1) / Number images used: 1094

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