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- EMDB-47838: Murine norovirus allosteric V339I escape mutant + calcium -

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Basic information

Entry
Database: EMDB / ID: EMD-47838
TitleMurine norovirus allosteric V339I escape mutant + calcium
Map dataMNV V339I plus calcium
Sample
  • Virus: Murine norovirus 1
    • Protein or peptide: Capsid protein VP1
  • Ligand: CALCIUM ION
Keywordsnorovirus / antibody / escape / calcium / allostery / VIRUS
Function / homologyCalicivirus coat protein C-terminal / Calicivirus coat protein C-terminal / Calicivirus coat protein / Calicivirus coat protein / virion component / Picornavirus/Calicivirus coat protein / Viral coat protein subunit / host cell cytoplasm / Capsid protein VP1
Function and homology information
Biological speciesMurine norovirus 1
Methodsingle particle reconstruction / cryo EM / Resolution: 2.6 Å
AuthorsSmith TJ / Sherman MB
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)NIH 1R01-AI141465 United States
CitationJournal: J Virol / Year: 2025
Title: Murine norovirus allosteric escape mutants mimic gut activation.
Authors: Michael B Sherman / Hong Q Smith / Faith Cox / Christiane E Wobus / Gillian C Lynch / B Montgomery Pettitt / Thomas J Smith /
Abstract: Murine norovirus (MNV) undergoes large conformational changes in response to the environment. The T=3 icosahedral capsid is composed of 180 copies of ~58 kDa VP1 that has N-terminal (N), shell (S), ...Murine norovirus (MNV) undergoes large conformational changes in response to the environment. The T=3 icosahedral capsid is composed of 180 copies of ~58 kDa VP1 that has N-terminal (N), shell (S), and C-terminal protruding (P) domains. In phosphate-buffered saline, the P domains are loosely tethered to the shell and float ~15 Å above the surface. At conditions found in the gut (i.e., low pH with high metal ion and bile salt concentrations), the P domain rotates and drops onto the shell with intra P domain changes that enhance receptor interactions while blocking antibody binding. Two of our monoclonal antibodies (2D3 and 4F9) have broad strain recognition, and the only escape mutants, V339I and D348E, are located on the C'D' loop and ~20 Å from the epitope. Here, we determined the cryo-EM structures of V339I and D348E at neutral pH +/-metal ions and bile salts. These allosteric escape mutants have the activated conformation in the absence of gut triggers. Since this conformation is not recognized by antibodies, it explains how these mutants evade antibody recognition. Dynamic simulations of the P domain further suggest that movement of the C'D' loop may be the rate-limiting step in the conformational change and that V339I increases the motion of the A'B'/E'F' loops compared to the wild-type (WT), facilitating the transition to the activated state. These findings have important implications for norovirus vaccine design since they uncover a form of the viral capsid that should lend superior immune protection against subsequent challenge by wild-type virus.IMPORTANCEImmune protection from norovirus infection is notoriously transient in both humans and mice. Our results strongly suggest that this is likely because the "activated" form of the virus found in gut conditions is not recognized by antibodies created in the circulation. By reversibly presenting one structure in the gut and a completely different antigenic structure in circulation, the gut tissue can be infected in subsequent challenges, while extraintestinal organs are protected. We find here that allosteric escape mutants to the most broadly neutralizing antibodies thwart recognition by transitioning to the activated state without the need for gut triggers (i.e., bile, low pH, or metal ions). These findings are significant because it is now feasible to present the activated form of the virus to the immune system (for example, as a vaccine) to better protect the gut tissue for longer periods of time.
History
DepositionNov 11, 2024-
Header (metadata) releaseMay 7, 2025-
Map releaseMay 7, 2025-
UpdateJul 2, 2025-
Current statusJul 2, 2025Processing site: RCSB / Status: Released

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Structure visualization

Downloads & links

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Map

FileDownload / File: emd_47838.map.gz / Format: CCP4 / Size: 600.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationMNV V339I plus calcium
Voxel sizeX=Y=Z: 1.1 Å
Density
Contour LevelBy AUTHOR: 0.35
Minimum - Maximum-8.079018 - 11.093514000000001
Average (Standard dev.)0.0029637315 (±0.4745209)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions540540540
Spacing540540540
CellA=B=C: 594.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Sample components

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Entire : Murine norovirus 1

EntireName: Murine norovirus 1
Components
  • Virus: Murine norovirus 1
    • Protein or peptide: Capsid protein VP1
  • Ligand: CALCIUM ION

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Supramolecule #1: Murine norovirus 1

SupramoleculeName: Murine norovirus 1 / type: virus / ID: 1 / Parent: 0 / Macromolecule list: #1 / NCBI-ID: 223997 / Sci species name: Murine norovirus 1 / Virus type: VIRION / Virus isolate: STRAIN / Virus enveloped: No / Virus empty: No

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Macromolecule #1: Capsid protein VP1

MacromoleculeName: Capsid protein VP1 / type: protein_or_peptide / ID: 1 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Murine norovirus 1
Molecular weightTheoretical: 58.583434 KDa
SequenceString: RMSDGAAPKA NGSEASGQDL VPAAVEQAVP IQPVAGAALA APAAGQINQI DPWIFQNFVQ CPLGEFSISP RNTPGEILFD LALGPGLNP YLAHLSAMYT GWVGNMEVQL VLAGNAFTAG KVVVALVPPY FPKGSLTTAQ ITCFPHVMCD VRTLEPIQLP L LDVRRVLW ...String:
RMSDGAAPKA NGSEASGQDL VPAAVEQAVP IQPVAGAALA APAAGQINQI DPWIFQNFVQ CPLGEFSISP RNTPGEILFD LALGPGLNP YLAHLSAMYT GWVGNMEVQL VLAGNAFTAG KVVVALVPPY FPKGSLTTAQ ITCFPHVMCD VRTLEPIQLP L LDVRRVLW HATQDQEESM RLVCMLYTPL RTNSPGDESF VVSGRLLSKP AADFNFVYLT PPIERTIYRM VDLPVIQPRL CT HARWPAP VYGLLVDPSL PSNPQWQNGR VHVDGTLLGT TPISGSWVSC FAAEAAYEFQ SGTGEVATFT LIEQDGSAYV PGD RAAPLG YPDFSGQLEI EIQTETTKTG DKLKVTTFEM ILGPTTNADQ APYQGRVFAS VTAAASLDLV DGRVRAVPRS IYGF QDTIP EYNDGLLVPL APPIGPFLPG EVLLRFRTYM RQIDTADAAA EAIDCALPQE FVSWFASNAF TVQSEALLLR YRNTL TGQL LFECKLYNEG YIALSYSGSG PLTFPTDGIF EVVSWVPRLY QLASVGSLAT GRMLKQ

UniProtKB: Capsid protein VP1

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Macromolecule #2: CALCIUM ION

MacromoleculeName: CALCIUM ION / type: ligand / ID: 2 / Number of copies: 3 / Formula: CA
Molecular weightTheoretical: 40.078 Da

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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

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 40.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.5 µm / Nominal defocus min: 1.5 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.6 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 164236
Initial angle assignmentType: PROJECTION MATCHING
Final angle assignmentType: PROJECTION MATCHING

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