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- PDB-6zml: CryoEM Structure of Merkel Cell Polyomavirus Virus-like Particle -

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Basic information

Entry
Database: PDB / ID: 6zml
TitleCryoEM Structure of Merkel Cell Polyomavirus Virus-like Particle
ComponentsCapsid protein VP1
KeywordsVIRUS LIKE PARTICLE / polyomavirus / capsid / Merkel cell carcinoma / jelly roll fold
Function / homology
Function and homology information


T=7 icosahedral viral capsid / endocytosis involved in viral entry into host cell / virion attachment to host cell / host cell nucleus / structural molecule activity / metal ion binding
Similarity search - Function
Capsid protein VP1,Polyomavirus / Polyomavirus Vp1; Chain A / Capsid protein VP1,Polyomavirus / Polyomavirus capsid protein VP1 superfamily / Polyomavirus coat protein / Double-stranded DNA virus, group I, capsid / Sandwich / Mainly Beta
Similarity search - Domain/homology
Biological speciesMerkel cell polyomavirus
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.4 Å
AuthorsBayer, N.J. / Januliene, D. / Stehle, T. / Moeller, A. / Blaum, B.S.
Funding support Germany, 3items
OrganizationGrant numberCountry
German Research Foundation (DFG)BL1294/3-1 Germany
German Research Foundation (DFG)FOR 2327 ViroCarb Germany
German Research Foundation (DFG)STE 1463/7-1 Germany
CitationJournal: J Virol / Year: 2020
Title: Structure of Merkel Cell Polyomavirus Capsid and Interaction with Its Glycosaminoglycan Attachment Receptor.
Authors: Niklas J Bayer / Dovile Januliene / Georg Zocher / Thilo Stehle / Arne Moeller / Bärbel S Blaum /
Abstract: Merkel cell polyomavirus (MCPyV) is a human double-stranded DNA tumor virus. MCPyV cell entry is unique among members of the polyomavirus family as it requires the engagement of two types of glycans, ...Merkel cell polyomavirus (MCPyV) is a human double-stranded DNA tumor virus. MCPyV cell entry is unique among members of the polyomavirus family as it requires the engagement of two types of glycans, sialylated oligosaccharides and sulfated glycosaminoglycans (GAGs). Here, we present crystallographic and cryo-electron microscopic structures of the icosahedral MCPyV capsid and analysis of its glycan interactions via nuclear magnetic resonance (NMR) spectroscopy. While sialic acid binding is specific for α2-3-linked sialic acid and mediated by the exposed apical loops of the major capsid protein VP1, a broad range of GAG oligosaccharides bind to recessed regions between VP1 capsomers. Individual VP1 capsomers are tethered to one another by an extensive disulfide network that differs in architecture from previously described interactions for other PyVs. An unusual C-terminal extension in MCPyV VP1 projects from the recessed capsid regions. Mutagenesis experiments show that this extension is dispensable for receptor interactions. The MCPyV genome was found to be clonally integrated in 80% of cases of Merkel cell carcinoma (MCC), a rare but aggressive form of human skin cancer, strongly suggesting that this virus is tumorigenic. In the metastasizing state, the course of the disease is often fatal, especially in immunocompromised individuals, as reflected by the high mortality rate of 33 to 46% and the low 5-year survival rate (<45%). The high seroprevalence of about 60% makes MCPyV a serious health care burden and illustrates the need for targeted treatments. In this study, we present the first high-resolution structural data for this human tumor virus and demonstrate that the full capsid is required for the essential interaction with its GAG receptor(s). Together, these data can be used as a basis for future strategies in drug development.
History
DepositionJul 3, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 5, 2020Provider: repository / Type: Initial release
Revision 1.1Oct 7, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.title / _citation_author.identifier_ORCID
Revision 1.2Oct 16, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / em_3d_fitting_list / em_admin / pdbx_entry_details / pdbx_initial_refinement_model / pdbx_modification_feature / pdbx_struct_oper_list
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _em_3d_fitting_list.accession_code / _em_3d_fitting_list.initial_refinement_model_id / _em_3d_fitting_list.source_name / _em_3d_fitting_list.type / _em_admin.last_update / _pdbx_struct_oper_list.name / _pdbx_struct_oper_list.symmetry_operation

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Structure visualization

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  • Simplified surface model + fitted atomic model
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Structure viewerMolecule:
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Assembly

Deposited unit
A: Capsid protein VP1
B: Capsid protein VP1
C: Capsid protein VP1
D: Capsid protein VP1
E: Capsid protein VP1
F: Capsid protein VP1


Theoretical massNumber of molelcules
Total (without water)279,6666
Polymers279,6666
Non-polymers00
Water00
1
A: Capsid protein VP1
B: Capsid protein VP1
C: Capsid protein VP1
D: Capsid protein VP1
E: Capsid protein VP1
F: Capsid protein VP1
x 60


Theoretical massNumber of molelcules
Total (without water)16,779,971360
Polymers16,779,971360
Non-polymers00
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
point symmetry operation59

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Components

#1: Protein
Capsid protein VP1 / VP1


Mass: 46611.031 Da / Num. of mol.: 6
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Merkel cell polyomavirus / Gene: VP1 / Plasmid: pwM / Cell line (production host): HEK293TT / Production host: Homo sapiens (human) / References: UniProt: B0G0W3
Has protein modificationY

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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: Merkel cell polyomavirus / Type: VIRUS / Entity ID: all / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Merkel cell polyomavirus
Source (recombinant)Organism: Homo sapiens (human) / Cell: HEK293TT / Plasmid: pwM
Details of virusEmpty: YES / Enveloped: NO / Isolate: OTHER / Type: VIRUS-LIKE PARTICLE
Natural hostOrganism: Homo sapiens
Virus shellDiameter: 508 nm / Triangulation number (T number): 7
Buffer solutionpH: 6.6 / Details: Solution was sterile filtered
Buffer component
IDConc.NameFormulaBuffer-ID
120 mMHEPESC8H18N2O4S1
2150 mMsodium chlorideNaCl1
31 mMcalcium chlorideCaCl21
SpecimenConc.: 1 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid type: C-flat-2/2
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 K

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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 / Nominal magnification: 75000 X / Nominal defocus max: 1500 nm / Nominal defocus min: 500 nm
Specimen holderCryogen: NITROGEN
Image recordingAverage exposure time: 67 sec. / Electron dose: 30 e/Å2 / Detector mode: COUNTING / Film or detector model: FEI FALCON III (4k x 4k) / Num. of grids imaged: 1 / Num. of real images: 463

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Processing

EM software
IDNameVersionCategory
1DoG Pickerparticle selection
2EPUimage acquisition
4CTFFIND4CTF correction
7UCSF Chimera1.11.2model fitting
9PHENIX1.14model refinement
10Coot0.8.9.1model refinement
11FREALIGNinitial Euler assignment
12cisTEMfinal Euler assignment
13cisTEMclassification
14cisTEM3D reconstruction
CTF correctionDetails: CTF correction was performed within 3D reconstruction
Type: NONE
Particle selectionNum. of particles selected: 23349
SymmetryPoint symmetry: I (icosahedral)
3D reconstructionResolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 22310 / Num. of class averages: 1 / Symmetry type: POINT
Atomic model buildingB value: 105.92 / Protocol: FLEXIBLE FIT / Space: REAL / Target criteria: Correlation coefficient
Atomic model building

3D fitting-ID: 1 / Accession code: 6ZLZ / Initial refinement model-ID: 1 / PDB-ID: 6ZLZ

6zlz

/ Source name: PDB / Type: experimental model

IDPdb chain-ID
1A
2B
3C
4D
5E
6F

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