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- EMDB-8842: Mouse norovirus complexed with Fabs from the IgA, 2D3, that cross... -

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Basic information

Entry
Database: EMDB / ID: EMD-8842
TitleMouse norovirus complexed with Fabs from the IgA, 2D3, that cross reacts with all tested strains
Map dataMouse norovirus complexed with Fab from a cross-reactive IgA
SampleMouse norovirus complexed with Fabs from the IgA, 2D3 != Murine norovirus

Mouse norovirus complexed with Fabs from the IgA, 2D3

  • Virus: Murine norovirus
Function / homology
Function and homology information


T=3 icosahedral viral capsid / virus-mediated perturbation of host defense response / host cell cytoplasm / identical protein binding
Similarity search - Function
Calicivirus coat protein C-terminal / Calicivirus coat protein C-terminal / Calicivirus coat protein / Calicivirus coat protein / Picornavirus/Calicivirus coat protein / Viral coat protein subunit
Similarity search - Domain/homology
Capsid protein / Capsid protein VP1
Similarity search - Component
Biological speciesMurine norovirus
Methodsingle particle reconstruction / cryo EM / Resolution: 8.7 Å
AuthorsSmith TJ
CitationJournal: mSphere / Year: 2017
Title: Norovirus Escape from Broadly Neutralizing Antibodies Is Limited to Allostery-Like Mechanisms.
Authors: Abimbola O Kolawole / Hong Q Smith / Sophia A Svoboda / Madeline S Lewis / Michael B Sherman / Gillian C Lynch / B Montgomery Pettitt / Thomas J Smith / Christiane E Wobus /
Abstract: Ideal antiviral vaccines elicit antibodies (Abs) with broad strain recognition that bind to regions that are difficult to mutate for escape. Using 10 murine norovirus (MNV) strains and 5 human ...Ideal antiviral vaccines elicit antibodies (Abs) with broad strain recognition that bind to regions that are difficult to mutate for escape. Using 10 murine norovirus (MNV) strains and 5 human norovirus (HuNoV) virus-like particles (VLPs), we identified monoclonal antibody (MAb) 2D3, which broadly neutralized all MNV strains tested. Importantly, escape mutants corresponding to this antibody were very slow to develop and were distal to those raised against our previously studied antibody, A6.2. To understand the atomic details of 2D3 neutralization, we determined the cryo-electron microscopy (cryo-EM) structure of the 2D3/MNV1 complex. Interestingly, 2D3 binds to the top of the P domain, very close to where A6.2 binds, but the only escape mutations identified to date fall well outside the contact regions of both 2D3 and A6.2. To determine how mutations in distal residues could block antibody binding, we used molecular dynamics flexible fitting simulations of the atomic structures placed into the density map to examine the 2D3/MNV1 complex and these mutations. Our findings suggest that the escape mutant, V339I, may stabilize a salt bridge network at the P-domain dimer interface that, in an allostery-like manner, affects the conformational relaxation of the P domain and the efficiency of binding. They further highlight the unusual antigenic surface bound by MAb 2D3, one which elicits cross-reactive antibodies but which the virus is unable to alter to escape neutralization. These results may be leveraged to generate norovirus (NoV) vaccines containing broadly neutralizing antibodies. The simplest and most common way for viruses to escape antibody neutralization is by mutating residues that are essential for antibody binding. Escape mutations are strongly selected for by their effect on viral fitness, which is most often related to issues of protein folding, particle assembly, and capsid function. The studies presented here demonstrated that a broadly neutralizing antibody to mouse norovirus binds to an exposed surface but that the only escape mutants that arose were distal to the antibody binding surface. To understand this finding, we performed an analysis that suggested that those escape mutations blocked antibody binding by affecting structural plasticity. This kind of antigenic region-one that gives rise to broadly neutralizing antibodies but that the virus finds difficult to escape from-is therefore ideal for vaccine development.
History
DepositionJul 21, 2017-
Header (metadata) releaseAug 16, 2017-
Map releaseAug 16, 2017-
UpdateNov 28, 2018-
Current statusNov 28, 2018Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 1
  • Imaged by UCSF Chimera
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  • Surface view colored by radius
  • Surface level: 1
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_8842.png

Downloads & links

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Map

FileDownload / File: emd_8842.map.gz / Format: CCP4 / Size: 244.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationMouse norovirus complexed with Fab from a cross-reactive IgA
Voxel sizeX=Y=Z: 1.49 Å
Density
Contour LevelBy AUTHOR: 1. / Movie #1: 1
Minimum - Maximum-4.2494187 - 4.7623925
Average (Standard dev.)0.02710175 (±0.9003104)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin-200-200-200
Dimensions400400400
Spacing400400400
CellA=B=C: 596.0 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.491.491.49
M x/y/z400400400
origin x/y/z0.0000.0000.000
length x/y/z596.000596.000596.000
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS-200-200-200
NC/NR/NS400400400
D min/max/mean-4.2494.7620.027

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Supplemental data

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Sample components

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Entire : Mouse norovirus complexed with Fabs from the IgA, 2D3

EntireName: Mouse norovirus complexed with Fabs from the IgA, 2D3
Components
  • Virus: Murine norovirus

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Supramolecule #1: Murine norovirus

SupramoleculeName: Murine norovirus / type: virus / ID: 1 / Parent: 0 / NCBI-ID: 357231 / Sci species name: Murine norovirus / Virus type: VIRION / Virus isolate: STRAIN / Virus enveloped: No / Virus empty: No
Host (natural)Organism: Mus musculus (house mouse)

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.4
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeJEOL 2200FS
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy
Image recordingFilm or detector model: DIRECT ELECTRON DE-20 (5k x 3k) / Average electron dose: 32.0 e/Å2

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Image processing

Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: PROJECTION MATCHING
Final reconstructionResolution.type: BY AUTHOR / Resolution: 8.7 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 2333

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