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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 / virus
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
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4 Å
AuthorsGeraets, J.A. / Flatt, J.W. / Domanska, A. / Butcher, S.J.
Funding supportFinland , 1件
OrganizationGrant numberCountry
European Union612308Finland
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 Report
SummaryFull reportAbout validation report
DateDeposition: Jul 5, 2018 / Release: Jun 5, 2019
RevisionDateData content typeGroupCategoryItemProviderType
1.0Jun 5, 2019Structure modelrepositoryInitial release
1.1Jun 12, 2019Structure modelData collectionem_admin / pdbx_database_proc_em_admin.last_update
1.2Jun 19, 2019Structure modelData collection / Database referencescitation / citation_author / em_admin / pdbx_database_proc_citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _em_admin.last_update

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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
Water0
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
point symmetry operation60
SymmetryPoint symmetry: (Schoenflies symbol: I (icosahedral))

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Components

#1: Protein/peptide 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, EC: 3.4.22.29, EC: 3.6.1.15, EC: 3.4.22.28, EC: 2.7.7.48
#2: Protein/peptide 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, EC: 3.4.22.29, EC: 3.6.1.15, EC: 3.4.22.28, EC: 2.7.7.48
#3: Protein/peptide 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, EC: 3.4.22.29, EC: 3.6.1.15, EC: 3.4.22.28, EC: 2.7.7.48
#4: Protein/peptide 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, EC: 3.4.22.29, EC: 3.6.1.15, EC: 3.4.22.28, EC: 2.7.7.48
#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 weight: 422Da Binding sites on capsid: 60
Entity ID: 1, 2, 3, 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

Buffer-ID: 1

IDConc.NameFormula
10.1 MMagnesium chlorideMgCl2
20.01 MHEPESC8H18N2O4S
SpecimenDetails: Inhibitor was added at 2500:1 molar ratio to purified CVB3 and incubated for 1h at 37C
Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
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 FIELDBright-field microscopy / Cs: 2.7 mm
Specimen holderModel: 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 µns / 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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