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- EMDB-0103: Identification of a druggable VP1-VP3 interprotomer pocket in the... -

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Entry
Database: EMDB / ID: EMD-0103
TitleIdentification of a druggable VP1-VP3 interprotomer pocket in the capsid of enteroviruses
Map data
SampleCoxsackievirus B3 (strain Nancy):
virus / (Capsid protein ...Capsid) x 4 / ligand
Function / homology
Function and homology information


positive regulation by virus of host cytokine production / modulation by virus of host NIK/NF-kappaB signaling / modulation by virus of host gene expression / suppression by virus of host translation initiation factor activity / positive stranded viral RNA replication / ec:3.4.22.29: / 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 / ec:3.4.22.28: ...positive regulation by virus of host cytokine production / modulation by virus of host NIK/NF-kappaB signaling / modulation by virus of host gene expression / suppression by virus of host translation initiation factor activity / positive stranded viral RNA replication / ec:3.4.22.29: / 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 / ec:3.4.22.28: / endocytosis involved in viral entry into host cell / RNA-protein covalent cross-linking / T=pseudo3 icosahedral viral capsid / host cell cytoplasmic vesicle membrane / pore formation by virus in membrane of host cell / integral to membrane of host cell / RNA helicase activity / ec:3.6.1.15: / suppression by virus of host gene expression / ec:2.7.7.48: / induction by virus of host autophagy / ion channel activity / protein complex oligomerization / viral RNA genome replication / cysteine-type endopeptidase activity / RNA-directed 5'-3' RNA polymerase activity / DNA replication / transcription, DNA-templated / host cell nucleus / virion attachment to host cell / structural molecule activity / RNA binding / membrane / ATP binding / metal ion binding
Picornavirus/Calicivirus coat protein / Helicase, superfamily 3, single-stranded RNA virus / Picornavirus 2B protein / Picornavirus capsid / RNA-directed RNA polymerase, C-terminal domain / Helicase, superfamily 3, single-stranded DNA/RNA virus / Peptidase C3A/C3B, picornaviral / Peptidase C3, picornavirus core protein 2A / Picornavirus coat protein VP4 superfamily / RNA-directed RNA polymerase, catalytic domain ...Picornavirus/Calicivirus coat protein / Helicase, superfamily 3, single-stranded RNA virus / Picornavirus 2B protein / Picornavirus capsid / RNA-directed RNA polymerase, C-terminal domain / Helicase, superfamily 3, single-stranded DNA/RNA virus / Peptidase C3A/C3B, picornaviral / Peptidase C3, picornavirus core protein 2A / Picornavirus coat protein VP4 superfamily / RNA-directed RNA polymerase, catalytic domain / picornavirus capsid protein / Poliovirus core protein 3a, soluble domain / 3C cysteine protease (picornain 3C) / Peptidase S1, PA clan / AAA+ ATPase domain / Picornavirus coat protein VP4 / RNA dependent RNA polymerase / Viral coat protein subunit / Picornavirales 3C/3C-like protease domain profile. / P-loop containing nucleoside triphosphate hydrolase / Superfamily 3 helicase of positive ssRNA viruses domain profile. / RNA helicase / RdRp of positive ssRNA viruses catalytic domain profile. / Picornavirus core protein 2A / Picornavirus 2B protein / Picornavirus coat protein (VP4) / Poliovirus 3A protein-like / Poliovirus 3A protein like
Genome polyprotein
Biological speciesCoxsackievirus B3 (strain Nancy)
Methodsingle particle reconstruction / cryo EM / Resolution: 4 Å
AuthorsGeraets JA / Flatt JW / Domanska A / Butcher SJ
CitationJournal: PLoS Biol. / Year: 2019
Title: A novel druggable interprotomer pocket in the capsid of rhino- and enteroviruses.
Authors: Rana Abdelnabi / James A Geraets / Yipeng Ma / Carmen Mirabelli / Justin W Flatt / Aušra Domanska / Leen Delang / Dirk Jochmans / Timiri Ajay Kumar / Venkatesan Jayaprakash / Barij Nayan Sinha / Pieter Leyssen / Sarah J Butcher / Johan Neyts /
Abstract: Rhino- and enteroviruses are important human pathogens, against which no antivirals are available. The best-studied inhibitors are "capsid binders" that fit in a hydrophobic pocket of the viral ...Rhino- and enteroviruses are important human pathogens, against which no antivirals are available. The best-studied inhibitors are "capsid binders" that fit in a hydrophobic pocket of the viral capsid. Employing a new class of entero-/rhinovirus inhibitors and by means of cryo-electron microscopy (EM), followed by resistance selection and reverse genetics, we discovered a hitherto unknown druggable pocket that is formed by viral proteins VP1 and VP3 and that is conserved across entero-/rhinovirus species. We propose that these inhibitors stabilize a key region of the virion, thereby preventing the conformational expansion needed for viral RNA release. A medicinal chemistry effort resulted in the identification of analogues targeting this pocket with broad-spectrum activity against Coxsackieviruses B (CVBs) and compounds with activity against enteroviruses (EV) of groups C and D, and even rhinoviruses (RV). Our findings provide novel insights in the biology of the entry of entero-/rhinoviruses and open new avenues for the design of broad-spectrum antivirals against these pathogens.
Validation ReportPDB-ID: 6gzv

SummaryFull reportAbout validation report
DateDeposition: Jul 5, 2018 / Header (metadata) release: Oct 24, 2018 / Map release: Jun 5, 2019 / Update: Jun 19, 2019

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.018
  • Imaged by UCSF Chimera
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  • Surface view colored by radius
  • Surface level: 0.018
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: : PDB-6gzv
  • Surface level: 0.018
  • Imaged by UCSF Chimera
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  • Simplified surface model + fitted atomic model
  • Atomic models: PDB-6gzv
  • Imaged by Jmol
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

Downloads & links

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Map

FileDownload / File: emd_0103.map.gz / Format: CCP4 / Size: 163.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.05 Å/pix.
x 350 pix.
= 366.8 Å
1.05 Å/pix.
x 350 pix.
= 366.8 Å
1.05 Å/pix.
x 350 pix.
= 366.8 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.048 Å
Density
Contour LevelBy AUTHOR: 0.018 / Movie #1: 0.018
Minimum - Maximum-0.051150657 - 0.1611951
Average (Standard dev.)0.0032831568 (±0.009124994)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions350350350
Spacing350350350
CellA=B=C: 366.8 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.0481.0481.048
M x/y/z350350350
origin x/y/z0.0000.0000.000
length x/y/z366.800366.800366.800
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS350350350
D min/max/mean-0.0510.1610.003

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Supplemental data

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Sample components

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Entire Coxsackievirus B3 (strain Nancy)

EntireName: Coxsackievirus B3 (strain Nancy)
Details: Coxsackievirus B3 (strain Nancy) NCBI Taxonomy ID: 103903 Full, non-enveloped virion from natural source Diameter: ~314A Triangulation: 1 (pT3) Benzene sulfonamide derivative Molecular weight: 422Da Binding sites on capsid: 60
Number of components: 6

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Component #1: virus, Coxsackievirus B3 (strain Nancy)

VirusName: Coxsackievirus B3 (strain Nancy) / Class: VIRION
Details: Coxsackievirus B3 (strain Nancy) NCBI Taxonomy ID: 103903 Full, non-enveloped virion from natural source Diameter: ~314A Triangulation: 1 (pT3) Benzene sulfonamide derivative Molecular weight: 422Da Binding sites on capsid: 60
Empty: No / Enveloped: No / Isolate: STRAIN
SpeciesSpecies: Coxsackievirus B3 (strain Nancy)
Source (natural)Host Species: Homo sapiens (human)

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Component #2: protein, Capsid protein VP1

ProteinName: Capsid protein VP1 / Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 31.639438 kDa
SourceSpecies: Coxsackievirus B3 (strain Nancy) / Strain: Nancy

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Component #3: protein, Capsid protein VP2

ProteinName: Capsid protein VP2 / Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 28.836502 kDa
SourceSpecies: Coxsackievirus B3 (strain Nancy) / Strain: Nancy

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Component #4: protein, Capsid protein VP3

ProteinName: Capsid protein VP3 / Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 26.195727 kDa
SourceSpecies: Coxsackievirus B3 (strain Nancy) / Strain: Nancy

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Component #5: protein, Capsid protein VP4

ProteinName: Capsid protein VP4 / Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 7.580377 kDa
SourceSpecies: Coxsackievirus B3 (strain Nancy) / Strain: Nancy

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Component #6: ligand, 4-[[4-[1,3-bis(oxidanylidene)isoindol-2-yl]phenyl]sulfony...

LigandName: 4-[[4-[1,3-bis(oxidanylidene)isoindol-2-yl]phenyl]sulfonylamino]benzoic acid
Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 0.422411 kDa

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Experimental details

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Sample preparation

SpecimenSpecimen state: Particle / Method: cryo EM
Sample solutionpH: 7.5
VitrificationInstrument: HOMEMADE PLUNGER / Cryogen 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: 47 e/Å2 / Illumination mode: FLOOD BEAM
LensCs: 2.7 mm / Imaging mode: BRIGHT FIELD
Specimen HolderModel: FEI TITAN KRIOS AUTOGRID HOLDER
CameraDetector: GATAN K2 SUMMIT (4k x 4k)

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Image acquisition

Image acquisitionSampling size: 5 µm

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Image processing

ProcessingMethod: single particle reconstruction / Applied symmetry: I (icosahedral) / Number of projections: 4891
3D reconstructionSoftware: RELION / Resolution: 4 Å / Resolution method: FSC 0.143 CUT-OFF
FSC plot (resolution estimation)

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Atomic model buiding

Modeling #1Refinement protocol: flexible / Refinement space: REAL
Output model

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