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- EMDB-18968: Cryo-EM structure of a coxsackievirus A6 virus-like particle -

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Basic information

Entry
Database: EMDB / ID: EMD-18968
TitleCryo-EM structure of a coxsackievirus A6 virus-like particle
Map dataMain map (globally sharpened)
Sample
  • Complex: Coxsackievirus A6 virus-like particle
    • Protein or peptide: Genome polyprotein
    • Protein or peptide: Genome polyprotein
    • Protein or peptide: Genome polyprotein
Keywordscoxsackievirus / virus-like particle / VIRUS LIKE PARTICLE
Function / homology
Function and homology information


: / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of MDA-5 activity / picornain 2A / symbiont-mediated suppression of host mRNA export from nucleus / symbiont genome entry into host cell via pore formation in plasma membrane / picornain 3C / T=pseudo3 icosahedral viral capsid / host cell cytoplasmic vesicle membrane / nucleoside-triphosphate phosphatase / channel activity ...: / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of MDA-5 activity / picornain 2A / symbiont-mediated suppression of host mRNA export from nucleus / symbiont genome entry into host cell via pore formation in plasma membrane / picornain 3C / T=pseudo3 icosahedral viral capsid / host cell cytoplasmic vesicle membrane / nucleoside-triphosphate phosphatase / channel activity / monoatomic ion transmembrane transport / DNA replication / RNA helicase activity / symbiont-mediated suppression of host gene expression / endocytosis involved in viral entry into host cell / symbiont-mediated activation of host autophagy / RNA-directed RNA polymerase / cysteine-type endopeptidase activity / viral RNA genome replication / RNA-directed RNA polymerase activity / DNA-templated transcription / virion attachment to host cell / host cell nucleus / structural molecule activity / ATP hydrolysis activity / proteolysis / RNA binding / ATP binding / metal ion binding / membrane
Similarity search - Function
Protein of unknown function DUF3724, picornavirus / Protein of unknown function (DUF3724) / Picornavirus coat protein / Poliovirus 3A protein-like / Poliovirus 3A protein like / Picornavirus 2B protein / Poliovirus core protein 3a, soluble domain / Picornavirus 2B protein / Peptidase C3, picornavirus core protein 2A / Picornavirus core protein 2A ...Protein of unknown function DUF3724, picornavirus / Protein of unknown function (DUF3724) / Picornavirus coat protein / Poliovirus 3A protein-like / Poliovirus 3A protein like / Picornavirus 2B protein / Poliovirus core protein 3a, soluble domain / Picornavirus 2B protein / Peptidase C3, picornavirus core protein 2A / Picornavirus core protein 2A / Picornavirus coat protein VP4 / Picornavirus coat protein (VP4) / Peptidase C3A/C3B, picornaviral / 3C cysteine protease (picornain 3C) / Picornavirales 3C/3C-like protease domain / Picornavirales 3C/3C-like protease domain profile. / Picornavirus capsid / picornavirus capsid protein / Helicase, superfamily 3, single-stranded RNA virus / Superfamily 3 helicase of positive ssRNA viruses domain profile. / Helicase, superfamily 3, single-stranded DNA/RNA virus / RNA helicase / Picornavirus/Calicivirus coat protein / Viral coat protein subunit / RNA-directed RNA polymerase, C-terminal domain / Viral RNA-dependent RNA polymerase / Reverse transcriptase/Diguanylate cyclase domain / RNA-directed RNA polymerase, catalytic domain / RdRp of positive ssRNA viruses catalytic domain profile. / ATPases associated with a variety of cellular activities / AAA+ ATPase domain / Peptidase S1, PA clan, chymotrypsin-like fold / Peptidase S1, PA clan / DNA/RNA polymerase superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
Biological speciesCoxsackievirus A6
Methodsingle particle reconstruction / cryo EM / Resolution: 3.15 Å
AuthorsGiannopoulou EA / Jakobi AJ
Funding supportEuropean Union, 1 items
OrganizationGrant numberCountry
European Research Council (ERC)European Union
CitationJournal: PLoS Pathog / Year: 2025
Title: Enterovirus-like particles encapsidate RNA and exhibit decreased stability due to lack of maturation.
Authors: Louis Kuijpers / Evdokia-Anastasia Giannopoulou / Yuzhen Feng / Wouter van den Braak / Abbas Freydoonian / Ramon Ramlal / Hugo Meiring / Belén Solano / Wouter H Roos / Arjen J Jakobi / Leo ...Authors: Louis Kuijpers / Evdokia-Anastasia Giannopoulou / Yuzhen Feng / Wouter van den Braak / Abbas Freydoonian / Ramon Ramlal / Hugo Meiring / Belén Solano / Wouter H Roos / Arjen J Jakobi / Leo A van der Pol / Nynke H Dekker /
Abstract: To counteract hand, foot, and mouth disease-causing viruses such as enterovirus A71 and coxsackievirus A6, virus-like particles (VLPs) have emerged as a leading contender for the development of a ...To counteract hand, foot, and mouth disease-causing viruses such as enterovirus A71 and coxsackievirus A6, virus-like particles (VLPs) have emerged as a leading contender for the development of a multivalent vaccine. However, VLPs have shown rapid conversion from a highly immunogenic state to a less immunogenic state and low particle integrity lifetimes compared to inactivated virus vaccines, thus raising concerns about their overall stability. Here, we produce VLPs to investigate capsid stability using cryogenic electron microscopy (cryo-EM), mass spectrometry (MS), biochemical assays, and atomic force microscopy (AFM). In contrast to prior studies and prevailing hypotheses, we show that insect-cell produced enterovirus VLPs include encapsidated RNA fragments with viral protein coding sequences. Our integrated approach reveals that CVA6 VLPs do not undergo viral maturation, in contrast to virions; that they can encapsidate RNA fragments, similarly to virions; and that despite the latter, they are more brittle than virions. Interestingly, this indicates that CVA6 VLP stability is more affected by lack of viral maturation than the presence of RNA. Our study highlights how the development of VLPs as vaccine candidates should encompass probing for unwanted (viral) RNA content and establishing control of their maturation to enhance stability.
History
DepositionNov 23, 2023-
Header (metadata) releaseOct 16, 2024-
Map releaseOct 16, 2024-
UpdateFeb 12, 2025-
Current statusFeb 12, 2025Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_18968.png

Downloads & links

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Map

FileDownload / File: emd_18968.map.gz / Format: CCP4 / Size: 512 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationMain map (globally sharpened)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.98 Å/pix.
x 512 pix.
= 499.2 Å		0.98 Å/pix.
x 512 pix.
= 499.2 Å		0.98 Å/pix.
x 512 pix.
= 499.2 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.975 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.22
Minimum - Maximum-0.6059197 - 1.0055261
Average (Standard dev.)-0.00038286136 (±0.05800266)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions512512512
Spacing512512512
CellA=B=C: 499.2 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_18968_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map B

Fileemd_18968_half_map_1.map
AnnotationHalf map B
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map A

Fileemd_18968_half_map_2.map
AnnotationHalf map A
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 : Coxsackievirus A6 virus-like particle

EntireName: Coxsackievirus A6 virus-like particle
Components
  • Complex: Coxsackievirus A6 virus-like particle
    • Protein or peptide: Genome polyprotein
    • Protein or peptide: Genome polyprotein
    • Protein or peptide: Genome polyprotein

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Supramolecule #1: Coxsackievirus A6 virus-like particle

SupramoleculeName: Coxsackievirus A6 virus-like particle / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Coxsackievirus A6
Molecular weightTheoretical: 5 MDa

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Macromolecule #1: Genome polyprotein

MacromoleculeName: Genome polyprotein / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO / EC number: picornain 2A
Source (natural)Organism: Coxsackievirus A6
Molecular weightTheoretical: 33.422234 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: DPIANAVENA VSALADTTIS RVTAASTAAS THSLGTGRVP ALQAAETGAS SNASDENLIE TRCVMNRNGV NEASVEHFYS RAGLVGVVE VKDSGTSLDG YTVWPIDVMG FVQQRRKLEL STYMRFDAEF TFVSNLNDST TPGMLLQYMY VPPGAPKPDS R KSYQWQTA ...String:
DPIANAVENA VSALADTTIS RVTAASTAAS THSLGTGRVP ALQAAETGAS SNASDENLIE TRCVMNRNGV NEASVEHFYS RAGLVGVVE VKDSGTSLDG YTVWPIDVMG FVQQRRKLEL STYMRFDAEF TFVSNLNDST TPGMLLQYMY VPPGAPKPDS R KSYQWQTA TNPSVFAKLS DPPPQVSVPF MSPATAYQWF YDGYPTFGEH KQATNLQYGQ CPNNMMGHFA IRTVSESTTG KN VHVRVYM RIKHVRAWVP RPLRSQAYMV KNYPTYSQTI TNTATDRASI TTTDYEGGVP ANPQRTS

UniProtKB: Genome polyprotein

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Macromolecule #2: Genome polyprotein

MacromoleculeName: Genome polyprotein / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO / EC number: picornain 2A
Source (natural)Organism: Coxsackievirus A6
Molecular weightTheoretical: 35.581648 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: MGAQVSTEKS GSHETKNVAT EGSTINFTNI NYYKDSYAAS ASRQDFAQDP AKFTRPVLDT IREVAAPLQS PSVEACGYSD RVAQLTVGN STITTQEAAN IVLSYGEWPE YCPSTDATAV DKPTRPDVSV NRFYTLSTKS WKTESTGWYW KFPDVLNDTG V FGQNAQFH ...String:
MGAQVSTEKS GSHETKNVAT EGSTINFTNI NYYKDSYAAS ASRQDFAQDP AKFTRPVLDT IREVAAPLQS PSVEACGYSD RVAQLTVGN STITTQEAAN IVLSYGEWPE YCPSTDATAV DKPTRPDVSV NRFYTLSTKS WKTESTGWYW KFPDVLNDTG V FGQNAQFH YLYRSGFCMH VQCNASKFHQ GALLVAAIPE FVVAASSPAT KPNGQGLYPD FAHTNPGKNG QEFRDPYVLD AG IPLSQAL VFPHQWINLR TNNCATIIMP YVNALPFDSA LNHSNFGLVV IPISPLKYCN GATTEVPITL TIAPLNSEFS GLR QAIKQ

UniProtKB: Genome polyprotein

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Macromolecule #3: Genome polyprotein

MacromoleculeName: Genome polyprotein / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO / EC number: picornain 2A
Source (natural)Organism: Coxsackievirus A6
Molecular weightTheoretical: 26.338787 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: GFPTELKPGT NQFLTTDDGT SPPILPGFEP TPLIHIPGEF TSLLDLCQIE TILEVNNTTS TTGVSRLLIP VRAQNNVDQL CASFQVDPG RNGPWQSTMV GQICRYYTQW SGSLKVTFMF TGSFMATGKM LIAYTPPGSA QPATREAAML GTHIVWDFGL Q SSVTLVIP ...String:
GFPTELKPGT NQFLTTDDGT SPPILPGFEP TPLIHIPGEF TSLLDLCQIE TILEVNNTTS TTGVSRLLIP VRAQNNVDQL CASFQVDPG RNGPWQSTMV GQICRYYTQW SGSLKVTFMF TGSFMATGKM LIAYTPPGSA QPATREAAML GTHIVWDFGL Q SSVTLVIP WISNTHFRAV KTGGVYDYYA TGIVTIWYQT NFVVPPDTPT EANIIALGAA QKNFTLKLCK DTDEIQQTAE YQ

UniProtKB: Genome polyprotein

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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: 7.4
Component:
ConcentrationFormulaName
0.137 MNaClSodium chloride
0.0027 MKClPotassium Chloride
0.01 MNa2HPO4Sodium Phosphate Dibasic
0.0018 MKH2PO4Potassium phosphate monobasic
25.0 %(w/v)C12H22O11Sucrose
GridModel: Quantifoil R2/1 / Material: COPPER / Mesh: 200 / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 90 sec. / Pretreatment - Atmosphere: AIR / Details: 18 mA
VitrificationCryogen name: ETHANE / Chamber humidity: 99 % / Chamber temperature: 20 K / Instrument: LEICA EM GP / Details: Blotting for 10 seconds from the carbon side.

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Electron microscopy

MicroscopeJEOL 3200FSC
TemperatureMin: 100.0 K / Max: 100.0 K
Specialist opticsEnergy filter - Name: In-column Omega Filter / Energy filter - Slit width: 20 eV
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: COUNTING / Digitization - Dimensions - Width: 3838 pixel / Digitization - Dimensions - Height: 3710 pixel / Digitization - Frames/image: 1-40 / Number grids imaged: 1 / Number real images: 1828 / Average exposure time: 9.0 sec. / Average electron dose: 58.24 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 50.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 4.1 mm / Nominal defocus max: 2.5 µm / Nominal defocus min: 0.5 µm / Nominal magnification: 40000
Sample stageSpecimen holder model: JEOL 3200FSC CRYOHOLDER / Cooling holder cryogen: NITROGEN

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Image processing

Particle selectionNumber selected: 62219
Startup modelType of model: OTHER / Details: Stochastic gradient descent
Final reconstructionApplied symmetry - Point group: I (icosahedral) / Algorithm: FOURIER SPACE / Resolution.type: BY AUTHOR / Resolution: 3.15 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 4.1.1) / Number images used: 44582
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4.1.1)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4.1.1)
Final 3D classificationNumber classes: 3 / Software - Name: cryoSPARC (ver. 4.1.1)
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial model
PDB IDChain

5yhq

chain_id: A, source_name: PDB, initial_model_type: experimental model

5yhq

chain_id: B, source_name: PDB, initial_model_type: experimental model

5yhq

chain_id: C, source_name: PDB, initial_model_type: experimental model
RefinementSpace: RECIPROCAL / Protocol: FLEXIBLE FIT / Overall B value: 130 / Target criteria: Average FSC
Output model

PDB-8r6x:
Cryo-EM structure of a coxsackievirus A6 virus-like particle

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