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- PDB-7k22: Murine polyomavirus pentavalent capsomer with 8A7H5 Fab, subparti... -

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Basic information

Entry
Database: PDB / ID: 7k22
TitleMurine polyomavirus pentavalent capsomer with 8A7H5 Fab, subparticle reconstruction
Components
  • 8A7H5 Fab heavy chain
  • 8A7H5 Fab light chain
  • Capsid protein VP1
KeywordsVIRAL PROTEIN / polyomavirus / capsomer
Function / homologyCapsid protein VP1,Polyomavirus / Polyomavirus capsid protein VP1 superfamily / Polyomavirus coat protein / Double-stranded DNA virus, group I, capsid / T=7 icosahedral viral capsid / host cell nucleus / virion attachment to host cell / structural molecule activity / Capsid protein VP1
Function and homology information
Biological speciesMus musculus polyomavirus 1
Rattus norvegicus (Norway rat)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsGoetschius, D.J. / Hafenstein, S.L.
Funding support United States, 6items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)R01NS088367 United States
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)R01NS092662 United States
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)R01AI107121 United States
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)F32NS106730 United States
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)F31NS083336 United States
National Institutes of Health/National Cancer Institute (NIH/NCI)T32CA060395 United States
CitationJournal: Elife / Year: 2020
Title: Antibody escape by polyomavirus capsid mutation facilitates neurovirulence.
Authors: Matthew D Lauver / Daniel J Goetschius / Colleen S Netherby-Winslow / Katelyn N Ayers / Ge Jin / Daniel G Haas / Elizabeth L Frost / Sung Hyun Cho / Carol M Bator / Stephanie M Bywaters / ...Authors: Matthew D Lauver / Daniel J Goetschius / Colleen S Netherby-Winslow / Katelyn N Ayers / Ge Jin / Daniel G Haas / Elizabeth L Frost / Sung Hyun Cho / Carol M Bator / Stephanie M Bywaters / Neil D Christensen / Susan L Hafenstein / Aron E Lukacher /
Abstract: JCPyV polyomavirus, a member of the human virome, causes progressive multifocal leukoencephalopathy (PML), an oft-fatal demyelinating brain disease in individuals receiving immunomodulatory therapies. ...JCPyV polyomavirus, a member of the human virome, causes progressive multifocal leukoencephalopathy (PML), an oft-fatal demyelinating brain disease in individuals receiving immunomodulatory therapies. Mutations in the major viral capsid protein, VP1, are common in JCPyV from PML patients (JCPyV-PML) but whether they confer neurovirulence or escape from virus-neutralizing antibody (nAb) in vivo is unknown. A mouse polyomavirus (MuPyV) with a sequence-equivalent JCPyV-PML VP1 mutation replicated poorly in the kidney, a major reservoir for JCPyV persistence, but retained the CNS infectivity, cell tropism, and neuropathology of the parental virus. This mutation rendered MuPyV resistant to a monoclonal Ab (mAb), whose specificity overlapped the endogenous anti-VP1 response. Using cryo-EM and a custom sub-particle refinement approach, we resolved an MuPyV:Fab complex map to 3.2 Å resolution. The structure revealed the mechanism of mAb evasion. Our findings demonstrate convergence between nAb evasion and CNS neurovirulence in vivo by a frequent JCPyV-PML VP1 mutation.
History
DepositionSep 8, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 7, 2020Provider: repository / Type: Initial release

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Structure visualization

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Structure viewerMolecule:
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Assembly

Deposited unit
L1: 8A7H5 Fab light chain
H1: 8A7H5 Fab heavy chain
F1: Capsid protein VP1
L2: 8A7H5 Fab light chain
H2: 8A7H5 Fab heavy chain
F2: Capsid protein VP1
L3: 8A7H5 Fab light chain
H3: 8A7H5 Fab heavy chain
F3: Capsid protein VP1
L4: 8A7H5 Fab light chain
H4: 8A7H5 Fab heavy chain
F4: Capsid protein VP1
L5: 8A7H5 Fab light chain
H5: 8A7H5 Fab heavy chain
F5: Capsid protein VP1


Theoretical massNumber of molelcules
Total (without water)338,98715
Polymers338,98715
Non-polymers00
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: microscopy
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area46980 Å2
ΔGint-289 kcal/mol
Surface area127960 Å2

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Components

#1: Antibody
8A7H5 Fab light chain


Mass: 12086.437 Da / Num. of mol.: 5 / Source method: isolated from a natural source / Source: (natural) Rattus norvegicus (Norway rat) / Plasmid details: hybridoma
#2: Antibody
8A7H5 Fab heavy chain


Mass: 13217.701 Da / Num. of mol.: 5 / Source method: isolated from a natural source / Source: (natural) Rattus norvegicus (Norway rat) / Plasmid details: hybridoma
#3: Protein
Capsid protein VP1 /


Mass: 42493.172 Da / Num. of mol.: 5
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus polyomavirus 1 / Production host: Mus musculoides (Temminck's mouse) / References: UniProt: A0A247D727

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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

Component
IDNameTypeDetailsEntity IDParent-IDSource
18A7H5 Fab light chain, 8A7H5 Fab heavy chain, Capsid protein VP1COMPLEXFab fragment generated from rat IgGall0RECOMBINANT
28A7H5 Fab light chain, 8A7H5 Fab heavy chainCOMPLEX#1-#21NATURAL
3Capsid protein VP1COMPLEX#31RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
23Murine polyomavirus strain A210636
12Rattus norvegicus (Norway rat)10116
Source (recombinant)Organism: Mus musculus (house mouse) / Cell: NMuMG
Details of virusEmpty: NO / Enveloped: NO / Isolate: STRAIN / Type: VIRION
Virus shellDiameter: 450 nm / Triangulation number (T number): 7
Buffer solutionpH: 7.9
Details: 10 mM HEPES pH 7.9, 1 mM CaCl2, 1 mM MgCl2, 5 mM KCl
SpecimenConc.: 2.8 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Details: MuPyV (2.8 mg/mL) was incubated with 8A7H5 Fab (1.1 mg/mL) for 30 m at room temperature
VitrificationCryogen 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: OTHER
Electron lensMode: BRIGHT FIELDBright-field microscopy
Image recordingElectron dose: 45 e/Å2 / Film or detector model: FEI FALCON III (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.17.1-3660_3260: / Classification: refinement
EM softwareName: RELION / Version: 3.1 / Category: 3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 109752 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00722225
ELECTRON MICROSCOPYf_angle_d0.71930290
ELECTRON MICROSCOPYf_dihedral_angle_d19.0112995
ELECTRON MICROSCOPYf_chiral_restr0.0473335
ELECTRON MICROSCOPYf_plane_restr0.0053905

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