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- PDB-6sk6: Cryo-EM structure of rhinovirus-B5 -

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Basic information

Entry
Database: PDB / ID: 6sk6
TitleCryo-EM structure of rhinovirus-B5
Components
  • Rhinovirus B5 VP1
  • Rhinovirus B5 VP2
  • Rhinovirus B5 VP3
  • Rhinovirus B5 VP4
KeywordsVIRUS / RV-A89 / HRV-B5 / capsid protein
Function / homology
Function and homology information


RNA-protein covalent cross-linking / : / 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 / ribonucleoside triphosphate phosphatase activity / T=pseudo3 icosahedral viral capsid / host cell cytoplasmic vesicle membrane / endocytosis involved in viral entry into host cell ...RNA-protein covalent cross-linking / : / 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 / ribonucleoside triphosphate phosphatase activity / T=pseudo3 icosahedral viral capsid / host cell cytoplasmic vesicle membrane / endocytosis involved in viral entry into host cell / cytoplasmic vesicle membrane / : / viral capsid / nucleoside-triphosphate phosphatase / protein complex oligomerization / monoatomic ion channel activity / host cell cytoplasm / RNA helicase activity / induction by virus of host autophagy / RNA-directed RNA polymerase / symbiont entry into host cell / symbiont-mediated suppression of host gene expression / viral RNA genome replication / cysteine-type endopeptidase activity / RNA-dependent RNA polymerase activity / DNA-templated transcription / structural molecule activity / virion attachment to host cell / proteolysis / RNA binding / ATP binding / metal ion binding / cytoplasm
Similarity search - Function
Jelly Rolls - #20 / 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 ...Jelly Rolls - #20 / 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) / Picornavirales 3C/3C-like protease domain / Picornavirales 3C/3C-like protease domain profile. / Peptidase C3A/C3B, picornaviral / 3C cysteine protease (picornain 3C) / 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. / Peptidase S1, PA clan, chymotrypsin-like fold / DNA/RNA polymerase superfamily / Peptidase S1, PA clan / Sandwich / P-loop containing nucleoside triphosphate hydrolase / Mainly Beta
Similarity search - Domain/homology
Genome polyprotein / Genome polyprotein / VP4
Similarity search - Component
Biological speciesHuman rhinovirus B5
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsWald, J. / Goessweiner-Mohr, N. / Blaas, D. / Pasin, M.
Funding support Austria, 1items
OrganizationGrant numberCountry
European Commission653706 Austria
CitationJournal: Proc Natl Acad Sci U S A / Year: 2019
Title: Cryo-EM structure of pleconaril-resistant rhinovirus-B5 complexed to the antiviral OBR-5-340 reveals unexpected binding site.
Authors: Jiri Wald / Marion Pasin / Martina Richter / Christin Walther / Neann Mathai / Johannes Kirchmair / Vadim A Makarov / Nikolaus Goessweiner-Mohr / Thomas C Marlovits / Irene Zanella / Antonio ...Authors: Jiri Wald / Marion Pasin / Martina Richter / Christin Walther / Neann Mathai / Johannes Kirchmair / Vadim A Makarov / Nikolaus Goessweiner-Mohr / Thomas C Marlovits / Irene Zanella / Antonio Real-Hohn / Nuria Verdaguer / Dieter Blaas / Michaela Schmidtke /
Abstract: Viral inhibitors, such as pleconaril and vapendavir, target conserved regions in the capsids of rhinoviruses (RVs) and enteroviruses (EVs) by binding to a hydrophobic pocket in viral capsid protein 1 ...Viral inhibitors, such as pleconaril and vapendavir, target conserved regions in the capsids of rhinoviruses (RVs) and enteroviruses (EVs) by binding to a hydrophobic pocket in viral capsid protein 1 (VP1). In resistant RVs and EVs, bulky residues in this pocket prevent their binding. However, recently developed pyrazolopyrimidines inhibit pleconaril-resistant RVs and EVs, and computational modeling has suggested that they also bind to the hydrophobic pocket in VP1. We studied the mechanism of inhibition of pleconaril-resistant RVs using RV-B5 (1 of the 7 naturally pleconaril-resistant rhinoviruses) and OBR-5-340, a bioavailable pyrazolopyrimidine with proven in vivo activity, and determined the 3D-structure of the protein-ligand complex to 3.6 Å with cryoelectron microscopy. Our data indicate that, similar to other capsid binders, OBR-5-340 induces thermostability and inhibits viral adsorption and uncoating. However, we found that OBR-5-340 attaches closer to the entrance of the pocket than most other capsid binders, whose viral complexes have been studied so far, showing only marginal overlaps of the attachment sites. Comparing the experimentally determined 3D structure with the control, RV-B5 incubated with solvent only and determined to 3.2 Å, revealed no gross conformational changes upon OBR-5-340 binding. The pocket of the naturally OBR-5-340-resistant RV-A89 likewise incubated with OBR-5-340 and solved to 2.9 Å was empty. Pyrazolopyrimidines have a rigid molecular scaffold and may thus be less affected by a loss of entropy upon binding. They interact with less-conserved regions than known capsid binders. Overall, pyrazolopyrimidines could be more suitable for the development of new, broadly active inhibitors.
History
DepositionAug 14, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 4, 2019Provider: repository / Type: Initial release
Revision 1.1Sep 11, 2019Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.pdbx_database_id_PubMed / _citation.title ..._citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2Sep 25, 2019Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Oct 2, 2019Group: Data collection / Derived calculations
Category: pdbx_point_symmetry / pdbx_struct_assembly ...pdbx_point_symmetry / pdbx_struct_assembly / pdbx_struct_assembly_gen / pdbx_struct_oper_list

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Structure visualization

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  • Biological unit as complete icosahedral assembly
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  • Biological unit as icosahedral pentamer
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  • Biological unit as icosahedral 23 hexamer
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  • Deposited structure unit
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  • Simplified surface model + fitted atomic model
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  • Superimposition on EM map
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Structure viewerMolecule:
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Assembly

Deposited unit
D: Rhinovirus B5 VP4
B: Rhinovirus B5 VP2
A: Rhinovirus B5 VP1
C: Rhinovirus B5 VP3


Theoretical massNumber of molelcules
Total (without water)93,2154
Polymers93,2154
Non-polymers00
Water0
1
D: Rhinovirus B5 VP4
B: Rhinovirus B5 VP2
A: Rhinovirus B5 VP1
C: Rhinovirus B5 VP3
x 60


Theoretical massNumber of molelcules
Total (without water)5,592,927240
Polymers5,592,927240
Non-polymers00
Water0
TypeNameSymmetry operationNumber
point symmetry operation60
Buried area18040 Å2
ΔGint-96 kcal/mol
Surface area32790 Å2
2


  • Idetical with deposited unit in distinct coordinate
  • icosahedral asymmetric unit
TypeNameSymmetry operationNumber
point symmetry operation1
3
D: Rhinovirus B5 VP4
B: Rhinovirus B5 VP2
A: Rhinovirus B5 VP1
C: Rhinovirus B5 VP3
x 5


  • icosahedral pentamer
  • 466 kDa, 20 polymers
Theoretical massNumber of molelcules
Total (without water)466,07720
Polymers466,07720
Non-polymers00
Water0
TypeNameSymmetry operationNumber
point symmetry operation5
4
D: Rhinovirus B5 VP4
B: Rhinovirus B5 VP2
A: Rhinovirus B5 VP1
C: Rhinovirus B5 VP3
x 6


  • icosahedral 23 hexamer
  • 559 kDa, 24 polymers
Theoretical massNumber of molelcules
Total (without water)559,29324
Polymers559,29324
Non-polymers00
Water0
TypeNameSymmetry operationNumber
point symmetry operation6
5


  • Idetical with deposited unit in distinct coordinate
  • icosahedral asymmetric unit, std point frame
TypeNameSymmetry operationNumber
transform to point frame1
SymmetryPoint symmetry: (Schoenflies symbol: I (icosahedral))

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Components

#1: Protein Rhinovirus B5 VP4


Mass: 7335.049 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Details: Virus grown in human cell line / Source: (natural) Human rhinovirus B5 / References: UniProt: Q80SQ3
#2: Protein Rhinovirus B5 VP2


Mass: 27507.256 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Details: Virus grown in human cell line / Source: (natural) Human rhinovirus B5
References: UniProt: B9V433, picornain 2A, nucleoside-triphosphate phosphatase, picornain 3C, RNA-directed RNA polymerase
#3: Protein Rhinovirus B5 VP1


Mass: 32743.861 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Details: Virus grown in human cell line / Source: (natural) Human rhinovirus B5 / References: UniProt: Q7T659
#4: Protein Rhinovirus B5 VP3


Mass: 25629.281 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Details: Virus grown in human cell line / Source: (natural) Human rhinovirus B5
References: UniProt: B9V433, picornain 2A, nucleoside-triphosphate phosphatase, picornain 3C, RNA-directed RNA polymerase

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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: Human rhinovirus B5 / Type: VIRUS / Entity ID: all / Source: NATURAL
Molecular weightExperimental value: NO
Source (natural)Organism: Human rhinovirus B5
Details of virusEmpty: NO / Enveloped: NO / Isolate: SEROTYPE / Type: VIRION
Natural hostOrganism: human
Virus shellName: VP1-4
Buffer solutionpH: 7.4
Buffer component
IDConc.NameBuffer-ID
1PBS1
210 %DMSODimethyl sulfoxide1
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid type: Quantifoil R2/2
VitrificationInstrument: FEI VITROBOT MARK III / Cryogen name: ETHANE / Humidity: 100 %

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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
Image recordingElectron dose: 56 e/Å2 / Detector mode: OTHER / Film or detector model: FEI FALCON III (4k x 4k) / Num. of real images: 1400
Image scansMovie frames/image: 25 / Used frames/image: 1-25

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Processing

EM software
IDNameVersionCategoryDetails
4CTFFIND4.1CTF correction
7Rosettamodel fittingcontrolled via StarMap v1.0
13Coot0.8.9.1model refinementmanual refinement
CTF correctionType: NONE
SymmetryPoint symmetry: C60 (60 fold cyclic)
3D reconstructionResolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 13656 / Symmetry type: POINT
Atomic model buildingSpace: REAL
Details: Rosetta: DiMaio, F. et al. Atomic-accuracy models from 4.5-A cryo-electron microscopy data with density-guided iterative local refinement. Nat. Meth (2015). doi:10.1038/nmeth.3286
Atomic model buildingPDB-ID: 1AYM

1aym

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