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- PDB-6gzv: Identification of a druggable VP1-VP3 interprotomer pocket in the... -

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Basic information

Entry
Database: PDB / ID: 6gzv
TitleIdentification of a druggable VP1-VP3 interprotomer pocket in the capsid of enteroviruses
Components
  • Capsid protein VP1
  • Capsid protein VP2
  • Capsid protein VP3
  • Capsid protein VP4
KeywordsVIRUS / Inhibitor / complex
Function / homology
Function and homology information


symbiont-mediated perturbation of host transcription / 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 / 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 / picornain 3C / T=pseudo3 icosahedral viral capsid / host cell cytoplasmic vesicle membrane ...symbiont-mediated perturbation of host transcription / 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 / 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 / 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 NF-kappaB cascade / 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
Jelly Rolls - #20 / Picornavirus coat protein VP4 superfamily / Picornavirus coat protein / 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 ...Jelly Rolls - #20 / Picornavirus coat protein VP4 superfamily / Picornavirus coat protein / 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 / Jelly Rolls / 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 / Sandwich / P-loop containing nucleoside triphosphate hydrolase / Mainly Beta
Similarity search - Domain/homology
Chem-FHK / Genome polyprotein
Similarity search - Component
Biological speciesCoxsackievirus B3
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4 Å
AuthorsGeraets, J.A. / Flatt, J.W. / Domanska, A. / Butcher, S.J.
Funding support Finland, 1items
OrganizationGrant numberCountry
European Union612308 Finland
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 ...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.
History
DepositionJul 5, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 5, 2019Provider: repository / Type: Initial release
Revision 1.1Jun 12, 2019Group: Data collection / Category: em_admin / pdbx_database_proc / Item: _em_admin.last_update
Revision 1.2Jun 19, 2019Group: Data collection / Database references
Category: citation / citation_author ...citation / citation_author / em_admin / pdbx_database_proc
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _em_admin.last_update
Revision 1.3May 15, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_struct_oper_list
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_oper_list.name / _pdbx_struct_oper_list.symmetry_operation / _pdbx_struct_oper_list.type

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Structure visualization

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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)94,6745
Polymers94,2524
Non-polymers4221
Water00
1
A: Capsid protein VP1
B: Capsid protein VP2
C: Capsid protein VP3
D: Capsid protein VP4
hetero molecules
x 60


Theoretical massNumber of molelcules
Total (without water)5,680,467300
Polymers5,655,123240
Non-polymers25,34560
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
point symmetry operation59
SymmetryPoint symmetry: (Schoenflies symbol: I (icosahedral))

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Components

#1: Protein Capsid protein VP1


Mass: 31639.438 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Coxsackievirus B3 (strain Nancy) / Strain: Nancy
References: UniProt: P03313, picornain 2A, nucleoside-triphosphate phosphatase, picornain 3C, RNA-directed RNA polymerase
#2: Protein Capsid protein VP2


Mass: 28836.502 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Coxsackievirus B3 (strain Nancy) / Strain: Nancy
References: UniProt: P03313, picornain 2A, nucleoside-triphosphate phosphatase, picornain 3C, RNA-directed RNA polymerase
#3: Protein Capsid protein VP3


Mass: 26195.727 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Coxsackievirus B3 (strain Nancy) / Strain: Nancy
References: UniProt: P03313, picornain 2A, nucleoside-triphosphate phosphatase, picornain 3C, RNA-directed RNA polymerase
#4: Protein Capsid protein VP4


Mass: 7580.377 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Coxsackievirus B3 (strain Nancy) / Strain: Nancy
References: UniProt: P03313, picornain 2A, nucleoside-triphosphate phosphatase, picornain 3C, RNA-directed RNA polymerase
#5: Chemical ChemComp-FHK / 4-[[4-[1,3-bis(oxidanylidene)isoindol-2-yl]phenyl]sulfonylamino]benzoic acid


Mass: 422.411 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H14N2O6S

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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 B3 (strain Nancy) / Type: VIRUS
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 ...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
Entity ID: #1-#4 / Source: NATURAL
Source (natural)Organism: Coxsackievirus B3 (strain Nancy)
Details of virusEmpty: NO / Enveloped: NO / Isolate: STRAIN / Type: VIRION
Natural hostOrganism: Homo sapiens
Virus shellDiameter: 314 nm / Triangulation number (T number): 1
Buffer solutionpH: 7.5
Buffer component
IDConc.NameFormulaBuffer-ID
10.1 MMagnesium chlorideMgCl21
20.01 MHEPESC8H18N2O4S1
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Details: Inhibitor was added at 2500:1 molar ratio to purified CVB3 and incubated for 1h at 37C
VitrificationInstrument: HOMEMADE PLUNGER / Cryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Cs: 2.7 mm
Specimen holderSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 47 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K2 SUMMIT (4k x 4k)
Image scansSampling size: 5 µm / Movie frames/image: 20

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Processing

EM software
IDNameVersionCategory
2EPU1.9.1image acquisition
4Gctf0.5CTF correction
9RELION2.0.4initial Euler assignment
10RELION2.1.betafinal Euler assignment
11RELION2.1.betaclassification
12RELION2.1.beta3D reconstruction
13MDFF0.5model refinement
14Coot0.8.8model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: I (icosahedral)
3D reconstructionResolution: 4 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 4891 / Symmetry type: POINT
Atomic model buildingProtocol: FLEXIBLE FIT / Space: REAL

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