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- EMDB-15727: Poliovirus type 2 (strain MEF-1) virus-like particle in complex w... -

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Basic information

Entry
Database: EMDB / ID: EMD-15727
TitlePoliovirus type 2 (strain MEF-1) virus-like particle in complex with capsid binder compound 17
Map dataLocal resolution scaled final map from RELION. Sharpened with an ad-hoc B-factor of -15A^2. Contour level determined in UCSF ChimeraX.
Sample
  • Virus: Human poliovirus 2
    • Protein or peptide: Capsid protein, VP1
    • Protein or peptide: Capsid protein, VP0
    • Protein or peptide: Capsid protein, VP3
  • Ligand: SPHINGOSINE
  • Ligand: 4-[[4-[1,3-bis(oxidanylidene)isoindol-2-yl]phenyl]sulfonylamino]benzoic acid
  • Ligand: water
KeywordsCapsid protein / VIRUS LIKE PARTICLE / inhibitor / complex
Function / homology
Function and homology information


symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of RIG-I activity / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of MDA-5 activity / receptor-mediated endocytosis of virus by host cell / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of MAVS activity / picornain 2A / symbiont-mediated suppression of host mRNA export from nucleus / symbiont genome entry into host cell via pore formation in plasma membrane / ribonucleoside triphosphate phosphatase activity / picornain 3C / T=pseudo3 icosahedral viral capsid ...symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of RIG-I activity / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of MDA-5 activity / receptor-mediated endocytosis of virus by host cell / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of MAVS activity / picornain 2A / symbiont-mediated suppression of host mRNA export from nucleus / symbiont genome entry into host cell via pore formation in plasma membrane / ribonucleoside triphosphate phosphatase activity / 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 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 / proteolysis / RNA binding / zinc ion binding / ATP binding / membrane
Similarity search - Function
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 ...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. / 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 speciesHuman poliovirus 2
Methodsingle particle reconstruction / cryo EM / Resolution: 1.88 Å
AuthorsBahar MW / Fry EE / Stuart DI
Funding support United States, 1 items
OrganizationGrant numberCountry
Bill & Melinda Gates FoundationRG.IMCB.I8-TSA-083 United States
CitationJournal: Commun Biol / Year: 2022
Title: A conserved glutathione binding site in poliovirus is a target for antivirals and vaccine stabilisation.
Authors: Mohammad W Bahar / Veronica Nasta / Helen Fox / Lee Sherry / Keith Grehan / Claudine Porta / Andrew J Macadam / Nicola J Stonehouse / David J Rowlands / Elizabeth E Fry / David I Stuart /
Abstract: Strategies to prevent the recurrence of poliovirus (PV) after eradication may utilise non-infectious, recombinant virus-like particle (VLP) vaccines. Despite clear advantages over inactivated or ...Strategies to prevent the recurrence of poliovirus (PV) after eradication may utilise non-infectious, recombinant virus-like particle (VLP) vaccines. Despite clear advantages over inactivated or attenuated virus vaccines, instability of VLPs can compromise their immunogenicity. Glutathione (GSH), an important cellular reducing agent, is a crucial co-factor for the morphogenesis of enteroviruses, including PV. We report cryo-EM structures of GSH bound to PV serotype 3 VLPs showing that it can enhance particle stability. GSH binds the positively charged pocket at the interprotomer interface shown recently to bind GSH in enterovirus F3 and putative antiviral benzene sulphonamide compounds in other enteroviruses. We show, using high-resolution cryo-EM, the binding of a benzene sulphonamide compound with a PV serotype 2 VLP, consistent with antiviral activity through over-stabilizing the interprotomer pocket, preventing the capsid rearrangements necessary for viral infection. Collectively, these results suggest GSH or an analogous tight-binding antiviral offers the potential for stabilizing VLP vaccines.
History
DepositionSep 4, 2022-
Header (metadata) releaseDec 7, 2022-
Map releaseDec 7, 2022-
UpdateJul 24, 2024-
Current statusJul 24, 2024Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_15727.png

Downloads & links

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Map

FileDownload / File: emd_15727.map.gz / Format: CCP4 / Size: 347.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationLocal resolution scaled final map from RELION. Sharpened with an ad-hoc B-factor of -15A^2. Contour level determined in UCSF ChimeraX.
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.83 Å/pix.
x 450 pix.
= 373.05 Å		0.83 Å/pix.
x 450 pix.
= 373.05 Å		0.83 Å/pix.
x 450 pix.
= 373.05 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.829 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.045
Minimum - Maximum-0.073327824 - 0.16575879
Average (Standard dev.)0.00019070733 (±0.011270358)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions450450450
Spacing450450450
CellA=B=C: 373.05 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: Half map from final refinement in RELION. Contour...

Fileemd_15727_half_map_1.map
AnnotationHalf map from final refinement in RELION. Contour level determined in UCSF ChimeraX.
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map from final refinement in RELION. Contour...

Fileemd_15727_half_map_2.map
AnnotationHalf map from final refinement in RELION. Contour level determined in UCSF ChimeraX.
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 poliovirus 2

EntireName: Human poliovirus 2
Components
  • Virus: Human poliovirus 2
    • Protein or peptide: Capsid protein, VP1
    • Protein or peptide: Capsid protein, VP0
    • Protein or peptide: Capsid protein, VP3
  • Ligand: SPHINGOSINE
  • Ligand: 4-[[4-[1,3-bis(oxidanylidene)isoindol-2-yl]phenyl]sulfonylamino]benzoic acid
  • Ligand: water

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Supramolecule #1: Human poliovirus 2

SupramoleculeName: Human poliovirus 2 / type: virus / ID: 1 / Parent: 0 / Macromolecule list: #1-#3
Details: Recombinantly expressed virus-like particle of PV2 (strain MEF-1)
NCBI-ID: 12083 / Sci species name: Human poliovirus 2 / Sci species strain: MEF-1 / Virus type: VIRUS-LIKE PARTICLE / Virus isolate: SEROTYPE / Virus enveloped: No / Virus empty: Yes
Host (natural)Organism: mammal environmental sample (environmental samples)
Molecular weightTheoretical: 5.81 MDa
Virus shellShell ID: 1 / Name: Virus shell 1 / Diameter: 310.0 Å / T number (triangulation number): 1

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Macromolecule #1: Capsid protein, VP1

MacromoleculeName: Capsid protein, VP1 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Human poliovirus 2 / Strain: MEF-1
Molecular weightTheoretical: 33.111207 KDa
Recombinant expressionOrganism: Mesocricetus auratus (golden hamster)
SequenceString: GLGDLIEGVV EGVTRNALTP LTPANNLPDT QSSGPAHSKE TPALTAVETG ATNPLVPSDT VQTRHVIQKR TRSESTVESF FARGACVAI IEVDNDAPTK RASKLFSVWK ITYKDTVQLR RKLEFFTYSR FDMEFTFVVT SNYTDANNGH ALNQVYQIMY I PPGAPIPG ...String:
GLGDLIEGVV EGVTRNALTP LTPANNLPDT QSSGPAHSKE TPALTAVETG ATNPLVPSDT VQTRHVIQKR TRSESTVESF FARGACVAI IEVDNDAPTK RASKLFSVWK ITYKDTVQLR RKLEFFTYSR FDMEFTFVVT SNYTDANNGH ALNQVYQIMY I PPGAPIPG KWNDYTWQTS SNPSVFYTYG APPARISVPY VGIANAYSHF YDGFAKVPLA GQASTEGDSL YGAASLNDFG SL AVRVVND HNPTKLTSKI RVYMKPKHVR VWCPRPPRAV PYYGPGVDYK DGLAPLPEKG LTTY

UniProtKB: Genome polyprotein

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Macromolecule #2: Capsid protein, VP0

MacromoleculeName: Capsid protein, VP0 / type: protein_or_peptide / ID: 2 / Details: Sequence is given for the VP0 polypeptide. / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Human poliovirus 2 / Strain: MEF-1
Molecular weightTheoretical: 37.456855 KDa
Recombinant expressionOrganism: Mesocricetus auratus (golden hamster)
SequenceString: MGAQVSSQKV GAHENSNRAY GGSTINYTTI NYYRDSASNA ASKQDFAQDP SKFTEPIKDV LIKTAPTLNS PNIEACGYSD RVMQLTLGN STITTQEAAN SVVAYGRWPE YIKDSEANPV DQPTEPDVAA CRFYTLDTVT WRKESRGWWW KLPDALKDMG L FGQNMFYH ...String:
MGAQVSSQKV GAHENSNRAY GGSTINYTTI NYYRDSASNA ASKQDFAQDP SKFTEPIKDV LIKTAPTLNS PNIEACGYSD RVMQLTLGN STITTQEAAN SVVAYGRWPE YIKDSEANPV DQPTEPDVAA CRFYTLDTVT WRKESRGWWW KLPDALKDMG L FGQNMFYH YLGRAGYTVH VQCNASKFHQ GALGVFAVPE MCLAGDSTTH MFTKYENANP GEKGGEFKGS FTLDTNATNP AR NFCPVDY LFGSGVLAGN AFVYPHQIIN LRTNNCATLV LPYVNSLSID SMTKHNNWGI AILPLAPLDF ATESSTEIPI TLT IAPMCC EFNGLRNITV PRTQ

UniProtKB: Genome polyprotein

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Macromolecule #3: Capsid protein, VP3

MacromoleculeName: Capsid protein, VP3 / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Human poliovirus 2 / Strain: MEF-1
Molecular weightTheoretical: 26.472293 KDa
Recombinant expressionOrganism: Mesocricetus auratus (golden hamster)
SequenceString: GLPVLNTPGS NQYLTADNYQ SPCAIPEFDV TPPIDIPGEV RNMMELAEID TMIPLNLTNQ RKNTMDMYRV ELNDAAHSDT PILCLSLSP ASDPRLAHTM LGEILNYYTH WAGSLKFTFL FCGSMMATGK LLVSYAPPGA EAPKSRKEAM LGTHVIWDIG L QSSCTMVV ...String:
GLPVLNTPGS NQYLTADNYQ SPCAIPEFDV TPPIDIPGEV RNMMELAEID TMIPLNLTNQ RKNTMDMYRV ELNDAAHSDT PILCLSLSP ASDPRLAHTM LGEILNYYTH WAGSLKFTFL FCGSMMATGK LLVSYAPPGA EAPKSRKEAM LGTHVIWDIG L QSSCTMVV PWISNTTYRQ TINDSFTEGG YISMFYQTRV VVPLSTPRKM DILGFVSACN DFSVRLLRDT THISQEAMPQ

UniProtKB: Genome polyprotein

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Macromolecule #4: SPHINGOSINE

MacromoleculeName: SPHINGOSINE / type: ligand / ID: 4 / Number of copies: 1 / Formula: SPH
Molecular weightTheoretical: 299.492 Da
Chemical component information

ChemComp-SPH:
SPHINGOSINE

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Macromolecule #5: 4-[[4-[1,3-bis(oxidanylidene)isoindol-2-yl]phenyl]sulfonylamino]b...

MacromoleculeName: 4-[[4-[1,3-bis(oxidanylidene)isoindol-2-yl]phenyl]sulfonylamino]benzoic acid
type: ligand / ID: 5 / Number of copies: 1 / Formula: FHK
Molecular weightTheoretical: 422.411 Da
Chemical component information

ChemComp-FHK:
4-[[4-[1,3-bis(oxidanylidene)isoindol-2-yl]phenyl]sulfonylamino]benzoic acid

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Macromolecule #6: water

MacromoleculeName: water / type: ligand / ID: 6 / Number of copies: 262 / Formula: HOH
Molecular weightTheoretical: 18.015 Da
Chemical component information

ChemComp-HOH:
WATER

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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

Concentration0.75 mg/mL
BufferpH: 7 / Component:
ConcentrationName
1.0 xDPBS
20.0 mMEDTA

Details: 1 x DPBS was made from tissue culture grade Dulbecco's Phosphate Buffered Saline (Sigma-Aldrich). 20 mM EDTA was prepared from fresh stocks of buffered EDTA.
GridModel: EMS Lacey Carbon / Material: COPPER / Mesh: 400 / Support film - Material: CARBON / Support film - topology: LACEY / Support film - Film thickness: 3 / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 30 sec. / Pretreatment - Atmosphere: AIR
Details: The specific type of grid used was Ultra-thin carbon support film, 3nm - on lacey carbon AGS187-4 from Agar Scientific.
VitrificationCryogen name: ETHANE-PROPANE / Chamber humidity: 100 % / Chamber temperature: 277.15 K / Instrument: FEI VITROBOT MARK IV
Details: Single blotting with 3.5ul of sample. Four second blot time and -17 blot force on the vitrobot..
DetailsRecombinant VLP of PV2 mixed with capsid inhibitor compound 17 at a molar ratio of 1:2500.

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Electron microscopy

MicroscopeTFS KRIOS
Specialist opticsEnergy filter - Name: GIF Quantum LS / Energy filter - Slit width: 20 eV
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Digitization - Dimensions - Width: 5760 pixel / Digitization - Dimensions - Height: 4092 pixel / Number grids imaged: 1 / Number real images: 4750 / Average exposure time: 1.7 sec. / Average electron dose: 34.68 e/Å2
Details: Images were collected in electron counting mode with a calibrated pixel size of 0.829 A/pixel. Super-resolution pixel size 0.4145 A/pixel. Movies were collected in 50 frames.
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 50.0 µm / Calibrated magnification: 60314 / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.3000000000000003 µm / Nominal defocus min: 0.8 µm / Nominal magnification: 105000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

DetailsAll frames were used for motion correction.
Particle selectionNumber selected: 157002
Details: Particle selection was automated with ETHAN particle picking software.
Startup modelType of model: OTHER
Details: Startup model was generated ab initio from a subset of the data (10%). Startup model was low pass filtered to 40 Angstroms.
Final reconstructionNumber classes used: 2 / Applied symmetry - Point group: I (icosahedral) / Algorithm: BACK PROJECTION / Resolution.type: BY AUTHOR / Resolution: 1.88 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 3.1.1)
Details: Final reconstruction was Ewald sphere corrected and sharpened with Post-processing in RELION using an inverse B-factor of -15.0 Angstroms. B-factor was selected ad-hoc while testing a range ...Details: Final reconstruction was Ewald sphere corrected and sharpened with Post-processing in RELION using an inverse B-factor of -15.0 Angstroms. B-factor was selected ad-hoc while testing a range of values for map interpretability.
Number images used: 51518
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 3.1.1)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 3.1.1)
Final 3D classificationNumber classes: 5 / Avg.num./class: 22600 / Software - Name: RELION (ver. 3.1.1)
Details: Number of particles selected for 3D classification was 113004.
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelPDB ID:

1eah


Chain - Source name: PDB / Chain - Initial model type: experimental model
DetailsInitial model was rigid body fitted using UCSF chimera and Coot. Global minimization and B-factor refinement was performed in real space using phenix_real.space.refine.
RefinementSpace: REAL / Protocol: RIGID BODY FIT / Target criteria: Correlation coefficient
Output model

PDB-8ayz:
Poliovirus type 2 (strain MEF-1) virus-like particle in complex with capsid binder compound 17

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