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- EMDB-6829: Cryo-EM Structure of CVA6 VLP -

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Entry
Database: EMDB / ID: 6829
TitleCryo-EM Structure of CVA6 VLP
Map data
SampleCoxsackievirus A6:
virus / (Capsid protein ...Capsid) x 3
Function / homologyPeptidase C3A/C3B, picornaviral / picornavirus capsid protein / Protein of unknown function DUF3724, picornavirus / Poliovirus 3A protein-like / Helicase, superfamily 3, single-stranded RNA virus / Peptidase S1, PA clan / RNA-directed RNA polymerase, catalytic domain / AAA+ ATPase domain / Picornavirus coat protein VP4 / Picornavirus 2B protein ...Peptidase C3A/C3B, picornaviral / picornavirus capsid protein / Protein of unknown function DUF3724, picornavirus / Poliovirus 3A protein-like / Helicase, superfamily 3, single-stranded RNA virus / Peptidase S1, PA clan / RNA-directed RNA polymerase, catalytic domain / AAA+ ATPase domain / Picornavirus coat protein VP4 / Picornavirus 2B protein / Picornavirus capsid / RNA-directed RNA polymerase, C-terminal domain / Helicase, superfamily 3, single-stranded DNA/RNA virus / Peptidase C3, picornavirus core protein 2A / Picornavirus/Calicivirus coat protein / Viral coat protein subunit / Poliovirus core protein 3a, soluble domain / P-loop containing nucleoside triphosphate hydrolase / Picornavirus core protein 2A / 3C cysteine protease (picornain 3C) / RNA dependent RNA polymerase / Superfamily 3 helicase of positive ssRNA viruses domain profile. / RdRp of positive ssRNA viruses catalytic domain profile. / Protein of unknown function (DUF3724) / Poliovirus 3A protein like / Picornavirus coat protein (VP4) / Picornavirus 2B protein / RNA helicase / T=pseudo3 icosahedral viral capsid / picornain 2A / pore-mediated entry of viral genome into host cell / suppression by virus of host mRNA export from nucleus / suppression by virus of host RIG-I activity / picornain 3C / endocytosis involved in viral entry into host cell / RNA-protein covalent cross-linking / host cell cytoplasmic vesicle membrane / pore formation by virus in membrane of host cell / integral to membrane of host cell / RNA helicase activity / nucleoside-triphosphatase / viral capsid / RNA-directed RNA polymerase / induction by virus of host autophagy / suppression by virus of host gene expression / ion channel activity / protein complex oligomerization / viral RNA genome replication / RNA-directed 5'-3' RNA polymerase activity / cysteine-type endopeptidase activity / virion attachment to host cell / transcription, DNA-templated / structural molecule activity / RNA binding / membrane / ATP binding / Genome polyprotein / Capsid protein VP1
Function and homology information
SourceCoxsackievirus A6
Methodsingle particle reconstruction / cryo EM / 3 Å resolution
AuthorsChen J / Zhang C / Huang Z / Cong Y
CitationJournal: J. Virol. / Year: 2018
Title: A 3.0-Angstrom Resolution Cryo-Electron Microscopy Structure and Antigenic Sites of Coxsackievirus A6-Like Particles.
Authors: Jinhuan Chen / Chao Zhang / Yu Zhou / Xiang Zhang / Chaoyun Shen / Xiaohua Ye / Wen Jiang / Zhong Huang / Yao Cong
Abstract: Coxsackievirus A6 (CVA6) has recently emerged as one of the predominant causative agents of hand, foot, and mouth disease (HFMD). The structure of the CVA6 mature viral particle has not been solved ...Coxsackievirus A6 (CVA6) has recently emerged as one of the predominant causative agents of hand, foot, and mouth disease (HFMD). The structure of the CVA6 mature viral particle has not been solved thus far. Our previous work shows that recombinant virus-like particles (VLPs) of CVA6 represent a promising CVA6 vaccine candidate. Here, we report the first cryo-electron microscopy (cryo-EM) structure of the CVA6 VLP at 3.0-Å resolution. The CVA6 VLP exhibits the characteristic features of enteroviruses but presents an open channel at the 2-fold axis and an empty, collapsed VP1 pocket, which is broadly similar to the structures of the enterovirus 71 (EV71) VLP and coxsackievirus A16 (CVA16) 135S expanded particle, indicating that the CVA6 VLP is in an expanded conformation. Structural comparisons reveal that two common salt bridges within protomers are maintained in the CVA6 VLP and other viruses of the genus, implying that these salt bridges may play a critical role in enteroviral protomer assembly. However, there are apparent structural differences among the CVA6 VLP, EV71 VLP, and CVA16 135S particle in the surface-exposed loops and C termini of subunit proteins, which are often antigenic sites for enteroviruses. By immunological assays, we identified two CVA6-specific linear B-cell epitopes (designated P42 and P59) located at the GH loop and the C-terminal region of VP1, respectively, in agreement with the structure-based prediction of antigenic sites. Our findings elucidate the structural basis and important antigenic sites of the CVA6 VLP as a strong vaccine candidate and also provide insight into enteroviral protomer assembly. Coxsackievirus A6 (CVA6) is becoming one of the major pathogens causing hand, foot, and mouth disease (HFMD), leading to significant morbidity and mortality in children and adults. However, no vaccine is currently available to prevent CVA6 infection. Our previous work shows that recombinant virus-like particles (VLPs) of CVA6 are a promising CVA6 vaccine candidate. Here, we present a 3.0-Å structure of the CVA6 VLP determined by cryo-electron microscopy. The overall architecture of the CVA6 VLP is similar to those of the expanded structures of enterovirus 71 (EV71) and coxsackievirus A16 (CVA16), but careful structural comparisons reveal significant differences in the surface-exposed loops and C termini of each capsid protein of these particles. In addition, we identified two CVA6-specific linear B-cell epitopes and mapped them to the GH loop and the C-terminal region of VP1, respectively. Collectively, our findings provide a structural basis and important antigenic information for CVA6 VLP vaccine development.
Validation ReportPDB-ID: 5yhq

SummaryFull reportAbout validation report
DateDeposition: Sep 29, 2017 / Header (metadata) release: Oct 25, 2017 / Map release: Oct 25, 2017 / Last update: Aug 22, 2018

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 1.8
  • Imaged by UCSF Chimera
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  • Surface view colored by radius
  • Surface level: 1.8
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: : PDB-5yhq
  • Surface level: 1.8
  • Imaged by UCSF Chimera
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  • Simplified surface model + fitted atomic model
  • Atomic models: PDB-5yhq
  • Imaged by Jmol
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

Downloads & links

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Map

Fileemd_6829.map.gz (map file in CCP4 format, 442369 KB)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
480 pix
0.82 Å/pix.
= 393.6 Å
480 pix
0.82 Å/pix.
= 393.6 Å
480 pix
0.82 Å/pix.
= 393.6 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.82 Å
Density
Contour Level:1.8 (by author), 1.8 (movie #1):
Minimum - Maximum-8.361276 - 15.031385999999999
Average (Standard dev.)0.0000016683748 (0.9999974)
Details

EMDB XML:

Space Group Number1
Map Geometry
Axis orderXYZ
Dimensions480480480
Origin-240.-240.-240.
Limit239.239.239.
Spacing480480480
CellA=B=C: 393.6 Å
α=β=γ: 90.0 deg.

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z0.820.820.82
M x/y/z480480480
origin x/y/z0.0000.0000.000
length x/y/z393.600393.600393.600
α/β/γ90.00090.00090.000
start NX/NY/NZ
NX/NY/NZ
MAP C/R/S123
start NC/NR/NS-240-240-240
NC/NR/NS480480480
D min/max/mean-8.36115.0310.000

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Supplemental data

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Sample components

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Entire Coxsackievirus A6

EntireName: Coxsackievirus A6 / Number of components: 4

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Component #1: virus, Coxsackievirus A6

VirusName: Coxsackievirus A6 / Class: VIRUS-LIKE PARTICLE / Empty: Yes / Enveloped: No / Isolate: OTHER
SpeciesSpecies: Coxsackievirus A6
Source (engineered)Expression System: Spodoptera frugiperda (fall armyworm)

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Component #2: protein, Capsid protein VP1

ProteinName: Capsid protein VP1 / Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 33.644395 kDa
SourceSpecies: Coxsackievirus A6
Source (engineered)Expression System: Spodoptera frugiperda (fall armyworm)

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Component #3: protein, Capsid protein VP3

ProteinName: Capsid protein VP3 / Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 26.375834 kDa
SourceSpecies: Coxsackievirus A6
Source (engineered)Expression System: Spodoptera frugiperda (fall armyworm)

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Component #4: protein, capsid protein VP0

ProteinName: capsid protein VP0 / Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 35.351426 kDa
SourceSpecies: Coxsackievirus A6
Source (engineered)Expression System: Spodoptera frugiperda (fall armyworm)

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Experimental details

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Sample preparation

SpecimenSpecimen state: particle / Method: cryo EM
Sample solutionpH: 7.2
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
ImagingMicroscope: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Electron dose: 42 e/Å2 / Illumination mode: FLOOD BEAM
LensImaging mode: BRIGHT FIELD
Specimen HolderModel: OTHER
CameraDetector: GATAN K2 SUMMIT (4k x 4k)

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Image processing

ProcessingMethod: single particle reconstruction / Number of projections: 11596
3D reconstructionResolution: 3 Å / Resolution method: FSC 0.143 CUT-OFF

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Atomic model buiding

Output model

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