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- EMDB-31223: FOOT AND MOUTH DISEASE VIRUS O/TIBET/99-BOUND THE SINGLE CHAIN FR... -

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Basic information

Entry
Database: EMDB / ID: EMD-31223
TitleFOOT AND MOUTH DISEASE VIRUS O/TIBET/99-BOUND THE SINGLE CHAIN FRAGMEN ANTIBODY C4
Map data
Sample
  • Complex: FMDV-OTi-C4
    • Complex: FOOT AND MOUTH DISEASE VIRUS O/TIBET/99
      • Protein or peptide: O/TIBET/99 VP1
      • Protein or peptide: O/TIBET/99 VP2
      • Protein or peptide: O/TIBET/99 VP3
      • Protein or peptide: O/TIBET/99 VP4
    • Complex: C4 scFv
      • Protein or peptide: Ig heavy chain variable region
      • Protein or peptide: Ig lamda chain variable region
Function / homology
Function and homology information


Immunoglobulin V-Type / Immunoglobulin V-set domain / Immunoglobulin V-set domain / Immunoglobulin subtype / Immunoglobulin / Ig-like domain profile. / Immunoglobulin-like domain / Immunoglobulin-like domain superfamily / Immunoglobulin-like fold
Similarity search - Domain/homology
Ig lamda chain variable region / Ig heavy chain variable region
Similarity search - Component
Biological speciesFoot-and-mouth disease virus / Bos taurus (cattle)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.75 Å
AuthorsHe Y / Li K
CitationJournal: J Virol / Year: 2021
Title: Two Cross-Protective Antigen Sites on Foot-and-Mouth Disease Virus Serotype O Structurally Revealed by Broadly Neutralizing Antibodies from Cattle.
Authors: Kun Li / Yong He / Li Wang / Pinghua Li / Sheng Wang / Pu Sun / Huifang Bao / Yimei Cao / Xuerong Liu / Guoqiang Zhu / Yali Song / Xingwen Bai / Xueqing Ma / Yuanfang Fu / Hong Yuan / Jing ...Authors: Kun Li / Yong He / Li Wang / Pinghua Li / Sheng Wang / Pu Sun / Huifang Bao / Yimei Cao / Xuerong Liu / Guoqiang Zhu / Yali Song / Xingwen Bai / Xueqing Ma / Yuanfang Fu / Hong Yuan / Jing Zhang / Jian Wang / Yingli Chen / Dong Li / Zhiyong Lou / Zaixin Liu / Zengjun Lu /
Abstract: Foot-and-mouth disease virus (FMDV) is a highly contagious virus that infects cloven-hoofed animals. Neutralizing antibodies play critical roles in antiviral infection. Although five known antigen ...Foot-and-mouth disease virus (FMDV) is a highly contagious virus that infects cloven-hoofed animals. Neutralizing antibodies play critical roles in antiviral infection. Although five known antigen sites that induce neutralizing antibodies have been defined, studies on cross-protective antigen sites are still scarce. We mapped two cross-protective antigen sites using 13 bovine-derived broadly neutralizing monoclonal antibodies (bnAbs) capable of neutralizing 4 lineages within 3 topotypes of FMDV serotype O. One antigen site was formed by a novel cluster of VP3-focused epitopes recognized by bnAb C4 and C4-like antibodies. The cryo-electron microscopy (cryo-EM) structure of the FMDV-OTi (O/Tibet/99)-C4 complex showed close contact with VP3 and a novel interprotomer antigen epitope around the icosahedral 3-fold axis of the FMDV particle, which is far beyond the known antigen site 4. The key determinants of the neutralizing function of C4 and C4-like antibodies on the capsid were βB (T65), the B-C loop (T68), the E-F loop (E131 and K134), and the H-I loop (G196), revealing a novel antigen site on VP3. The other antigen site comprised two group epitopes on VP2 recognized by 9 bnAbs (B57, B73, B77, B82, F28, F145, F150, E46, and E54), which belong to the known antigen site 2 of FMDV serotype O. Notably, bnAb C4 potently promoted FMDV RNA release in response to damage to viral particles, suggesting that the targeted epitope contains a trigger mechanism for particle disassembly. This study revealed two cross-protective antigen sites that can elicit cross-reactive neutralizing antibodies in cattle and provided new structural information for the design of a broad-spectrum molecular vaccine against FMDV serotype O. FMDV is the causative agent of foot-and-mouth disease (FMD), which is one of the most contagious and economically devastating diseases of domestic animals. The antigenic structure of FMDV serotype O is rather complicated, especially for those sites that can elicit a cross-protective neutralizing antibody response. Monoclonal neutralization antibodies provide both crucial defense components against FMDV infection and valuable tools for fine analysis of the antigenic structure. In this study, we found a cluster of novel VP3-focused epitopes using 13 bnAbs against FMDV serotype O from natural host cattle, which revealed two cross-protective antigen sites on VP2 and VP3. Antibody C4 targeting this novel epitope potently promoted viral particle disassembly and RNA release before infection, which may indicate a vulnerable region of FMDV. This study reveals new structural information about cross-protective antigen sites of FMDV serotype O, providing valuable and strong support for future research on broad-spectrum vaccines against FMD.
History
DepositionApr 21, 2021-
Header (metadata) releaseAug 18, 2021-
Map releaseAug 18, 2021-
UpdateFeb 23, 2022-
Current statusFeb 23, 2022Processing site: PDBj / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.023
  • Imaged by UCSF Chimera
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  • Surface view colored by radius
  • Surface level: 0.023
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7eo0
  • Surface level: 0.023
  • Imaged by UCSF Chimera
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  • Simplified surface model + fitted atomic model
  • Atomic modelsPDB-7eo0
  • Imaged by Jmol
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_31223.png

Downloads & links

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Map

FileDownload / File: emd_31223.map.gz / Format: CCP4 / Size: 421.9 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 0.93 Å
Density
Contour LevelBy AUTHOR: 0.023 / Movie #1: 0.023
Minimum - Maximum-0.08626129 - 0.12984553
Average (Standard dev.)0.0012814581 (±0.008495394)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin-239-239-239
Dimensions480480480
Spacing480480480
CellA=B=C: 446.4 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z0.930.930.93
M x/y/z480480480
origin x/y/z0.0000.0000.000
length x/y/z446.400446.400446.400
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ500500500
MAP C/R/S123
start NC/NR/NS-239-239-239
NC/NR/NS480480480
D min/max/mean-0.0860.1300.001

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Supplemental data

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Sample components

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Entire : FMDV-OTi-C4

EntireName: FMDV-OTi-C4
Components
  • Complex: FMDV-OTi-C4
    • Complex: FOOT AND MOUTH DISEASE VIRUS O/TIBET/99
      • Protein or peptide: O/TIBET/99 VP1
      • Protein or peptide: O/TIBET/99 VP2
      • Protein or peptide: O/TIBET/99 VP3
      • Protein or peptide: O/TIBET/99 VP4
    • Complex: C4 scFv
      • Protein or peptide: Ig heavy chain variable region
      • Protein or peptide: Ig lamda chain variable region

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Supramolecule #1: FMDV-OTi-C4

SupramoleculeName: FMDV-OTi-C4 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all

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Supramolecule #2: FOOT AND MOUTH DISEASE VIRUS O/TIBET/99

SupramoleculeName: FOOT AND MOUTH DISEASE VIRUS O/TIBET/99 / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1-#4
Source (natural)Organism: Foot-and-mouth disease virus

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Supramolecule #3: C4 scFv

SupramoleculeName: C4 scFv / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #5-#6
Source (natural)Organism: Bos taurus (cattle)
Recombinant expressionOrganism: Escherichia coli BL21 (bacteria) / Recombinant strain: BL21

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Macromolecule #1: O/TIBET/99 VP1

MacromoleculeName: O/TIBET/99 VP1 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Foot-and-mouth disease virus
Molecular weightTheoretical: 23.524781 KDa
SequenceString: TTSTGESADP VTATVENYGG ETQVQRRQHT DVSFILDRFV KVTPKDQINV LDLMQTPAHT LVGALLRTAT YYFADLEVAV KHEGNLTWV PNGAPETALD NTTNPTAYHK APLTRLALPY TAPHRVLATV YNGNCKYGES PVTNARGDLQ VLAQKAARAL P TSFNYGAI ...String:
TTSTGESADP VTATVENYGG ETQVQRRQHT DVSFILDRFV KVTPKDQINV LDLMQTPAHT LVGALLRTAT YYFADLEVAV KHEGNLTWV PNGAPETALD NTTNPTAYHK APLTRLALPY TAPHRVLATV YNGNCKYGES PVTNARGDLQ VLAQKAARAL P TSFNYGAI KATRVTELLY RMKRAETYCP RPLLAIHPSE ARHKQKIVAP VKQLL

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Macromolecule #2: O/TIBET/99 VP2

MacromoleculeName: O/TIBET/99 VP2 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Foot-and-mouth disease virus
Molecular weightTheoretical: 24.338387 KDa
SequenceString: DKKTEETTLL EDRILTTRNG HTTSTTQSSV GVTYGYATAE DFVSGPNTSG LETRVVQAER FFKTHLFDWV TSDPFGRCYQ LELPTDHKG VYGSLTDSYA YMRNGWDVEV TAVGNQFNGG CLLVAMVPEL CSIDKRGLYQ LTLFPHQFIN PRTNMTAHIT V PFVGVNRY ...String:
DKKTEETTLL EDRILTTRNG HTTSTTQSSV GVTYGYATAE DFVSGPNTSG LETRVVQAER FFKTHLFDWV TSDPFGRCYQ LELPTDHKG VYGSLTDSYA YMRNGWDVEV TAVGNQFNGG CLLVAMVPEL CSIDKRGLYQ LTLFPHQFIN PRTNMTAHIT V PFVGVNRY DQYKVHKPWT LVVMVVAPLT VNTEGAPQIK VYANIAPTNV HVAGEFPSKE

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Macromolecule #3: O/TIBET/99 VP3

MacromoleculeName: O/TIBET/99 VP3 / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Foot-and-mouth disease virus
Molecular weightTheoretical: 23.875801 KDa
SequenceString: GIFPVACSDG YGGLVTTDPK TADPAYGKVF NPPRNMLPGR FTNFLDVAEA CPTFLHFEGD VPYVTTKTDS DRVLAQFDLS LAAKHMSNT FLAGLAQYYT QYSGTINLHF MFTGPTDAKA RYMIAYAPPG MEPPKTPEAA AHCIHAEWDT GLNSKFTFSI P YLSAADYA ...String:
GIFPVACSDG YGGLVTTDPK TADPAYGKVF NPPRNMLPGR FTNFLDVAEA CPTFLHFEGD VPYVTTKTDS DRVLAQFDLS LAAKHMSNT FLAGLAQYYT QYSGTINLHF MFTGPTDAKA RYMIAYAPPG MEPPKTPEAA AHCIHAEWDT GLNSKFTFSI P YLSAADYA YTASDAAETT NVQGWVCLFQ ITHGKADGDA LVVLASAGKD FELRLPVDAR TQ

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Macromolecule #4: O/TIBET/99 VP4

MacromoleculeName: O/TIBET/99 VP4 / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Foot-and-mouth disease virus
Molecular weightTheoretical: 8.778129 KDa
SequenceString:
GAGQSSPATG SQNQSGNTGS IINNYYMQQY QNSMDTQLGD NAISGGSNEG STDTTSTHTT NTQNNDWFSK LASSAFSGLF GALLA

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Macromolecule #5: Ig heavy chain variable region

MacromoleculeName: Ig heavy chain variable region / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Bos taurus (cattle)
Molecular weightTheoretical: 13.914535 KDa
Recombinant expressionOrganism: Escherichia coli BL21 (bacteria)
SequenceString:
QVQLRESGPS LVKPSQTLFL TCTVSGFSLT SYSVNWVRQT PGKMLECLGG IATSGSTGYN PVLKSRLRIT KDNSKSQVSL SVSNVTPED TATYYCAKWS SRGGYDCGVH SSDYSYLDAW GQGLLVTVSS

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Macromolecule #6: Ig lamda chain variable region

MacromoleculeName: Ig lamda chain variable region / type: protein_or_peptide / ID: 6 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Bos taurus (cattle)
Molecular weightTheoretical: 12.79488 KDa
Recombinant expressionOrganism: Escherichia coli BL21 (bacteria)
SequenceString:
WAQAVLTQPS SVSASLGQRV SITCSGSSSN IGRYGATWYQ QVPGSGLRTI IYGSSRRPSG VPDRFSGSKS GNTVTLTISS LQPEDEADY FCAAYDISTN AVFGSGTTLT LLGDYKDDDD KGG

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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

MicroscopeFEI TALOS ARCTICA
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: OTHER
Image recordingFilm or detector model: FEI FALCON II (4k x 4k) / Average electron dose: 50.0 e/Å2
Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company

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Image processing

Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.75 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 14458

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