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- EMDB-50614: Coxsackievirus A9 bound with compound 15 (CL278) -

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Basic information

Entry
Database: EMDB / ID: EMD-50614
TitleCoxsackievirus A9 bound with compound 15 (CL278)
Map dataDensity map of Coxsackievirus A9 bound with compound 15 (CL278) obtained by cryoEM and single-particle processing in cryoSPARC at global resolution 2.58 A.
Sample
  • Virus: Coxsackievirus A9
    • Protein or peptide: Capsid protein VP1
    • Protein or peptide: Capsid protein VP2
    • Protein or peptide: Capsid protein VP3
    • Protein or peptide: Capsid protein VP4
  • Ligand: ~{N}-[(4-fluorophenyl)methyl]-4-[(4-methylpiperazin-1-yl)methyl]aniline
  • Ligand: MYRISTIC ACID
KeywordsAntiviral / capsid stabilizer / hydrophobic pocket / cryoEM / VIRUS
Function / homology
Function and homology information


symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of RIG-I 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 / endocytosis involved in viral entry into host cell / nucleoside-triphosphate phosphatase / channel activity ...symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of RIG-I 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 / endocytosis involved in viral entry into host cell / nucleoside-triphosphate phosphatase / channel activity / monoatomic ion transmembrane transport / DNA replication / RNA helicase activity / induction by virus of host autophagy / RNA-directed RNA polymerase / viral RNA genome replication / cysteine-type endopeptidase activity / RNA-dependent RNA polymerase activity / virus-mediated perturbation of host defense response / DNA-templated transcription / host cell nucleus / virion attachment to host cell / structural molecule activity / ATP hydrolysis activity / proteolysis / RNA binding / ATP binding / membrane / metal ion binding
Similarity search - Function
Picornavirus coat protein VP4 superfamily / 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) ...Picornavirus coat protein VP4 superfamily / 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 speciesHuman coxsackievirus A9 (strain Griggs) / Coxsackievirus A9
Methodsingle particle reconstruction / cryo EM / Resolution: 2.58 Å
AuthorsPlavec Z / Butcher SJ / Mitchell C / Buckner C
Funding support Finland, 3 items
OrganizationGrant numberCountry
Academy of Finland315950 Finland
Sigrid Juselius Foundation95-7202-38 Finland
Jane and Aatos Erkko Foundation Finland
CitationJournal: J Med Chem / Year: 2024
Title: SAR Analysis of Novel Coxsackie virus A9 Capsid Binders.
Authors: Chiara Tammaro / Zlatka Plavec / Laura Myllymäki / Cristopher Mitchell / Sara Consalvi / Mariangela Biava / Alessia Ciogli / Aušra Domanska / Valtteri Leppilampi / Cienna Buckner / Simone ...Authors: Chiara Tammaro / Zlatka Plavec / Laura Myllymäki / Cristopher Mitchell / Sara Consalvi / Mariangela Biava / Alessia Ciogli / Aušra Domanska / Valtteri Leppilampi / Cienna Buckner / Simone Manetto / Pietro Sciò / Antonio Coluccia / Mira Laajala / Giulio M Dondio / Chiara Bigogno / Varpu Marjomäki / Sarah J Butcher / Giovanna Poce /
Abstract: Enterovirus infections are common in humans, yet there are no approved antiviral treatments. In this study we concentrated on inhibition of one of the (EV-B), namely Coxsackievirus A9 (CVA9), using ...Enterovirus infections are common in humans, yet there are no approved antiviral treatments. In this study we concentrated on inhibition of one of the (EV-B), namely Coxsackievirus A9 (CVA9), using a combination of medicinal chemistry, virus inhibition assays, structure determination from cryogenic electron microscopy and molecular modeling, to determine the structure activity relationships for a promising class of novel -phenylbenzylamines. Of the new 29 compounds synthesized, 10 had half maximal effective concentration (EC) values between 0.64-10.46 μM, and of these, 7 had 50% cytotoxicity concentration (CC) values higher than 200 μM. In addition, this new series of compounds showed promising physicochemical properties and act through capsid stabilization, preventing capsid expansion and subsequent release of the genome.
History
DepositionJun 11, 2024-
Header (metadata) releaseOct 2, 2024-
Map releaseOct 2, 2024-
UpdateOct 23, 2024-
Current statusOct 23, 2024Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_50614.png

Downloads & links

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Map

FileDownload / File: emd_50614.map.gz / Format: CCP4 / Size: 347.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationDensity map of Coxsackievirus A9 bound with compound 15 (CL278) obtained by cryoEM and single-particle processing in cryoSPARC at global resolution 2.58 A.
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.97 Å/pix.
x 450 pix.
= 436.5 Å		0.97 Å/pix.
x 450 pix.
= 436.5 Å		0.97 Å/pix.
x 450 pix.
= 436.5 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.97 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.2
Minimum - Maximum-0.5001951 - 1.2949054
Average (Standard dev.)0.01813015 (±0.118653856)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions450450450
Spacing450450450
CellA=B=C: 436.5 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: Half map of Coxsackievirus A9 bound with compound...

Fileemd_50614_half_map_1.map
AnnotationHalf map of Coxsackievirus A9 bound with compound 15 (CL278) obtained by cryoEM and single-particle processing in cryoSPARC.
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map of Coxsackievirus A9 bound with compound...

Fileemd_50614_half_map_2.map
AnnotationHalf map of Coxsackievirus A9 bound with compound 15 (CL278) obtained by cryoEM and single-particle processing in cryoSPARC.
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Coxsackievirus A9

EntireName: Coxsackievirus A9
Components
  • Virus: Coxsackievirus A9
    • Protein or peptide: Capsid protein VP1
    • Protein or peptide: Capsid protein VP2
    • Protein or peptide: Capsid protein VP3
    • Protein or peptide: Capsid protein VP4
  • Ligand: ~{N}-[(4-fluorophenyl)methyl]-4-[(4-methylpiperazin-1-yl)methyl]aniline
  • Ligand: MYRISTIC ACID

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Supramolecule #1: Coxsackievirus A9

SupramoleculeName: Coxsackievirus A9 / type: virus / ID: 1 / Parent: 0 / Macromolecule list: #1-#4
Details: Coxsackievirus A9 was propagated on green monkey kidney cells and purified on a sucrose gradient.
NCBI-ID: 12067 / Sci species name: Coxsackievirus A9 / Sci species strain: Griggs / Virus type: VIRION / Virus isolate: STRAIN / Virus enveloped: No / Virus empty: No
Host (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 8 MDa
Virus shellShell ID: 1 / Name: icosahedral capsid / Diameter: 300.0 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 coxsackievirus A9 (strain Griggs)
Molecular weightTheoretical: 33.86902 KDa
SequenceString: GDVEEAIERA VVHVADTMRS GPSNSASVPA LTAVETGHTS QVTPSDTMQT RHVKNYHSRS ESTVENFLGR SACVYMEEYK TTDNDVNKK FVAWPINTKQ MVQMRRKLEM FTYLRFDMEV TFVITSRQDP GTTLAQDMPV LTHQIMYVPP GGPIPAKVDD Y AWQTSTNP ...String:
GDVEEAIERA VVHVADTMRS GPSNSASVPA LTAVETGHTS QVTPSDTMQT RHVKNYHSRS ESTVENFLGR SACVYMEEYK TTDNDVNKK FVAWPINTKQ MVQMRRKLEM FTYLRFDMEV TFVITSRQDP GTTLAQDMPV LTHQIMYVPP GGPIPAKVDD Y AWQTSTNP SIFWTEGNAP ARMSIPFISI GNAYSNFYDG WSNFDQRGSY GYNTLNNLGH IYVRHVSGSS PHPITSTIRV YF KPKHTRA WVPRPPRLCQ YKKAFSVDFT PTPITDTRKD INTVTTVAQS RRRGDMSTLN TH

UniProtKB: Genome polyprotein

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Macromolecule #2: Capsid protein VP2

MacromoleculeName: Capsid protein VP2 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Human coxsackievirus A9 (strain Griggs)
Molecular weightTheoretical: 27.791363 KDa
SequenceString: SDRVRSITLG NSTITTQECA NVVVGYGRWP TYLRDDEATA EDQPTQPDVA TCRFYTLDSI KWEKGSVGWW WKFPEALSDM GLFGQNMQY HYLGRAGYTI HVQCNASKFH QGCLLVVCVP EAEMGGAVVG QAFSATAMAN GDKAYEFTSA TQSDQTKVQT A IHNAGMGV ...String:
SDRVRSITLG NSTITTQECA NVVVGYGRWP TYLRDDEATA EDQPTQPDVA TCRFYTLDSI KWEKGSVGWW WKFPEALSDM GLFGQNMQY HYLGRAGYTI HVQCNASKFH QGCLLVVCVP EAEMGGAVVG QAFSATAMAN GDKAYEFTSA TQSDQTKVQT A IHNAGMGV GVGNLTIYPH QWINLRTNNS ATIVMPYINS VPMDNMFRHY NFTLMVIPFV KLDYADTAST YVPITVTVAP MC AEYNGLR LAQA

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 coxsackievirus A9 (strain Griggs)
Molecular weightTheoretical: 26.335072 KDa
SequenceString: GLPTMNTPGS TQFLTSDDFQ SPCALPQFDV TPSMNIPGEV KNLMEIAEVD SVVPVNNVQD TTDQMEMFRI PVTINAPLQQ QVFGLRLQP GLDSVFKHTL LGEILNYYAH WSGSMKLTFV FCGSAMATGK FLIAYSPPGA NPPKTRKDAM LGTHIIWDIG L QSSCVLCV ...String:
GLPTMNTPGS TQFLTSDDFQ SPCALPQFDV TPSMNIPGEV KNLMEIAEVD SVVPVNNVQD TTDQMEMFRI PVTINAPLQQ QVFGLRLQP GLDSVFKHTL LGEILNYYAH WSGSMKLTFV FCGSAMATGK FLIAYSPPGA NPPKTRKDAM LGTHIIWDIG L QSSCVLCV PWISQTHYRL VQQDEYTSAG YVTCWYQTGM IVPPGTPNSS SIMCFASACN DFSVRMLRDT PFISQDNKLQ

UniProtKB: Genome polyprotein

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Macromolecule #4: Capsid protein VP4

MacromoleculeName: Capsid protein VP4 / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Human coxsackievirus A9 (strain Griggs)
Molecular weightTheoretical: 7.352039 KDa
SequenceString:
GAQVSTQKTG AHETSLSAAG NSIIHYTNIN YYKDAASNSA NRQDFTQDPS KFTEPVKDVM IKSLPALN

UniProtKB: Genome polyprotein

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Macromolecule #5: ~{N}-[(4-fluorophenyl)methyl]-4-[(4-methylpiperazin-1-yl)methyl]a...

MacromoleculeName: ~{N}-[(4-fluorophenyl)methyl]-4-[(4-methylpiperazin-1-yl)methyl]aniline
type: ligand / ID: 5 / Number of copies: 1 / Formula: A1IEI
Molecular weightTheoretical: 313.412 Da

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Macromolecule #6: MYRISTIC ACID

MacromoleculeName: MYRISTIC ACID / type: ligand / ID: 6 / Number of copies: 1 / Formula: MYR
Molecular weightTheoretical: 228.371 Da
Chemical component information

ChemComp-MYR:
MYRISTIC ACID

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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

Concentration0.4 mg/mL
BufferpH: 7.2
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 300 / Support film - Material: CARBON / Support film - topology: HOLEY / Support film - Film thickness: 2 / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 45 sec.
VitrificationCryogen name: ETHANE / Chamber humidity: 85 % / Chamber temperature: 295.15 K / Instrument: LEICA EM GP / Details: Sample was blotted from the front for 1.5 s..
DetailsCompound 15 (CL278) was solubilized in DMSO and diluted to the final concentration in PBS + 2 mM MgCl2. Purified Coxsackievirus A9 was incubated with compound 15 (CL278) for 1h at 37C after which the sample was vitrified on a semi-automatic plunger Leica EM GP on copper Quantifoil R1.2/1.3 grids with holey carbon film and 300 mesh. This sample was monodisperse.

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Electron microscopy

MicroscopeFEI TALOS ARCTICA
TemperatureMin: 93.15 K / Max: 103.15 K
Image recordingFilm or detector model: FEI FALCON III (4k x 4k) / Detector mode: COUNTING / Digitization - Dimensions - Width: 1496 pixel / Digitization - Dimensions - Height: 1496 pixel / Number grids imaged: 1 / Number real images: 618 / Average exposure time: 1.0 sec. / Average electron dose: 40.0 e/Å2
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsCalibrated defocus max: 2.9 µm / Calibrated defocus min: 0.4 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 3.0 µm / Nominal defocus min: 0.5 µm / Nominal magnification: 150000
Sample stageCooling holder cryogen: NITROGEN
Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 14445
Startup modelType of model: OTHER
Details: Initial model was generated in cryoSPARC utilising Ab Initio model protocol.
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.58 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 4.2.0)
Software - details: Non-uniform refinement job in cryoSPARC was used for final reconstruction angle assignment
Number images used: 2558
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4.2.0)
Software - details: Protocol for Ab Initio implemented in cryoSPARC was used for model creation
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final 3D classificationSoftware - Name: RELION (ver. 3) / Software - details: 3D classification
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelPDB ID:

8at5


Chain - Source name: PDB / Chain - Initial model type: experimental model
RefinementOverall B value: 82
Output model

PDB-9fo2:
Coxsackievirus A9 bound with compound 15 (CL278)

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