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

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Basic information

Entry
Database: PDB / ID: 9fo2
TitleCoxsackievirus A9 bound with compound 15 (CL278)
Components(Capsid protein ...) x 4
KeywordsVIRUS / Antiviral / capsid stabilizer / hydrophobic pocket / cryoEM
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
: / MYRISTIC ACID / Genome polyprotein
Similarity search - Component
Biological speciesHuman coxsackievirus A9
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.58 Å
AuthorsPlavec, Z. / Butcher, S.J. / Mitchell, C. / Buckner, C.
Funding support Finland, 3items
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, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 2, 2024Provider: repository / Type: Initial release
Revision 1.1Oct 23, 2024Group: Data collection / Database references / Structure summary
Category: citation / citation_author ...citation / citation_author / em_admin / pdbx_entry_details
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID / _em_admin.last_update / _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Capsid protein VP1
B: Capsid protein VP2
C: Capsid protein VP3
D: Capsid protein VP4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)95,8896
Polymers95,3474
Non-polymers5422
Water00
1
A: Capsid protein VP1
B: Capsid protein VP2
C: Capsid protein VP3
D: Capsid protein VP4
hetero molecules
x 60


  • defined by author&software
  • Evidence: electron microscopy, not applicable
  • 5.75 MDa, 240 polymers
Theoretical massNumber of molelcules
Total (without water)5,753,357360
Polymers5,720,850240
Non-polymers32,507120
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
point symmetry operation59

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Components

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Capsid protein ... , 4 types, 4 molecules ABCD

#1: Protein Capsid protein VP1 / P1D / Virion protein 1


Mass: 33869.020 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Human coxsackievirus A9 (strain Griggs) / Cell line: gmk / References: UniProt: P21404
#2: Protein Capsid protein VP2 / P1B / Virion protein 2


Mass: 27791.363 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Human coxsackievirus A9 (strain Griggs) / Cell line: gmk / References: UniProt: P21404
#3: Protein Capsid protein VP3 / P1C / Virion protein 3


Mass: 26335.072 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Human coxsackievirus A9 (strain Griggs) / Cell line: gmk / References: UniProt: P21404
#4: Protein Capsid protein VP4 / Capsid protein VP4


Mass: 7352.039 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Human coxsackievirus A9 (strain Griggs) / Cell line: gmk / References: UniProt: P21404

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Non-polymers , 2 types, 2 molecules

#5: Chemical ChemComp-A1IEI / ~{N}-[(4-fluorophenyl)methyl]-4-[(4-methylpiperazin-1-yl)methyl]aniline


Mass: 313.412 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H24FN3 / Feature type: SUBJECT OF INVESTIGATION
#6: Chemical ChemComp-MYR / MYRISTIC ACID


Mass: 228.371 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H28O2

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Details

Has ligand of interestY
Has protein modificationN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Coxsackievirus A9 / Type: VIRUS
Details: Coxsackievirus A9 was propagated on green monkey kidney cells and purified on a sucrose gradient.
Entity ID: #1-#4 / Source: NATURAL
Molecular weightValue: 8 MDa / Experimental value: NO
Source (natural)Organism: Coxsackievirus A9 / Strain: Griggs
Details of virusEmpty: NO / Enveloped: NO / Isolate: STRAIN / Type: VIRION
Natural hostOrganism: Homo sapiens
Virus shellName: icosahedral capsid / Diameter: 300 nm / Triangulation number (T number): 1
Buffer solutionpH: 7.2
SpecimenConc.: 0.4 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Details: Compound 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 ...Details: Compound 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.
Specimen supportGrid material: COPPER / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: LEICA EM GP / Cryogen name: ETHANE / Humidity: 85 % / Chamber temperature: 295.15 K / Details: Sample was blotted from the front for 1.5 s.

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Electron microscopy imaging

Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company
MicroscopyModel: FEI TALOS ARCTICA
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 150000 X / Nominal defocus max: 3000 nm / Nominal defocus min: 500 nm / Calibrated defocus min: 400 nm / Calibrated defocus max: 2900 nm
Specimen holderCryogen: NITROGEN / Temperature (max): 103.15 K / Temperature (min): 93.15 K
Image recordingAverage exposure time: 1 sec. / Electron dose: 40 e/Å2 / Detector mode: COUNTING / Film or detector model: FEI FALCON III (4k x 4k) / Num. of grids imaged: 1 / Num. of real images: 618
Image scansWidth: 1496 / Height: 1496

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Processing

EM software
IDNameVersionCategoryDetails
1cryoSPARC4.2.0particle selectionsmall set of particles was picked using manual picker; template was made from manually picked particles using 2D classification; Template picker was used to pick particles form all micrographs; 2D classification was used to separate particles from other structures
2EPU2.11.0.2354RELimage acquisition
4cryoSPARC4.2.0CTF correctionPatch CTF correction was used with default parameters
7UCSF ChimeraX1.5model fitting
9cryoSPARC4.2.0initial Euler assignmentProtocol for Ab Initio implemented in cryoSPARC was used for model creation
11RELION3classification3D classification
12cryoSPARC4.2.03D reconstructionNon-uniform refinement job in cryoSPARC was used for final reconstruction angle assignment
13PHENIX1.20.1model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 14445
3D reconstructionResolution: 2.58 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 2558 / Symmetry type: POINT
Atomic model buildingB value: 82
Atomic model buildingPDB-ID: 8at5

8at5


Accession code: 8at5 / Source name: PDB / Type: experimental model

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