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- PDB-7fei: Complex of FMDV A/WH/CHA/09 and bovine neutralizing scFv antibody R55 -

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Basic information

Entry
Database: PDB / ID: 7fei
TitleComplex of FMDV A/WH/CHA/09 and bovine neutralizing scFv antibody R55
Components
  • (Capsid protein ...Capsid) x 4
  • IG HEAVY CHAIN VARIABLE REGION
  • IG LAMDA CHAIN VARIABLE REGION
KeywordsVIRUS
Function / homology
Function and homology information


: / L-peptidase / icosahedral viral capsid / modulation by virus of host chromatin organization / positive stranded viral RNA replication / RNA-protein covalent cross-linking / : / ribonucleoside triphosphate phosphatase activity / picornain 3C / T=pseudo3 icosahedral viral capsid ...: / L-peptidase / icosahedral viral capsid / modulation by virus of host chromatin organization / positive stranded viral RNA replication / RNA-protein covalent cross-linking / : / ribonucleoside triphosphate phosphatase activity / picornain 3C / T=pseudo3 icosahedral viral capsid / host cell cytoplasmic vesicle membrane / endocytosis involved in viral entry into host cell / viral capsid / : / nucleoside-triphosphate phosphatase / regulation of translation / protein complex oligomerization / monoatomic ion channel activity / clathrin-dependent endocytosis of virus by host cell / host cell cytoplasm / RNA helicase activity / viral protein processing / induction by virus of host autophagy / symbiont entry into host cell / RNA-directed RNA polymerase / viral RNA genome replication / cysteine-type endopeptidase activity / RNA-dependent RNA polymerase activity / DNA-templated transcription / virion attachment to host cell / structural molecule activity / RNA binding / ATP binding / membrane / cytoplasm
Similarity search - Function
Aphthovirus leader protease (L(pro)) domain profile. / Peptidase C28, foot-and-mouth virus L-proteinase / Foot-and-mouth virus L-proteinase / Foot-and-mouth disease virus VP1 coat / Capsid protein VP4, Picornavirus / Viral protein VP4 subunit / Capsid protein VP4 superfamily, Picornavirus / Helicase/polymerase/peptidase polyprotein, Calicivirus-type / Picornavirales 3C/3C-like protease domain / Picornavirales 3C/3C-like protease domain profile. ...Aphthovirus leader protease (L(pro)) domain profile. / Peptidase C28, foot-and-mouth virus L-proteinase / Foot-and-mouth virus L-proteinase / Foot-and-mouth disease virus VP1 coat / Capsid protein VP4, Picornavirus / Viral protein VP4 subunit / Capsid protein VP4 superfamily, Picornavirus / Helicase/polymerase/peptidase polyprotein, Calicivirus-type / Picornavirales 3C/3C-like protease domain / Picornavirales 3C/3C-like protease domain profile. / Peptidase C3A/C3B, picornaviral / 3C cysteine protease (picornain 3C) / Picornavirus capsid / picornavirus capsid protein / Helicase, superfamily 3, single-stranded RNA virus / Superfamily 3 helicase of positive ssRNA viruses domain profile. / Helicase, superfamily 3, single-stranded DNA/RNA virus / RNA helicase / Papain-like cysteine peptidase superfamily / Picornavirus/Calicivirus coat protein / Viral coat protein subunit / RNA-directed RNA polymerase, C-terminal domain / Viral RNA-dependent RNA polymerase / Reverse transcriptase/Diguanylate cyclase domain / RNA-directed RNA polymerase, catalytic domain / RdRp of positive ssRNA viruses catalytic domain profile. / Peptidase S1, PA clan, chymotrypsin-like fold / Peptidase S1, PA clan / DNA/RNA polymerase superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
Capsid protein VP0 / Capsid protein VP0 / Genome polyprotein / Capsid protein VP0
Similarity search - Component
Biological speciesBos taurus (cattle)
Foot-and-mouth disease virus - type A
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.91 Å
AuthorsHe, Y. / Li, K. / Lou, Z.
CitationJournal: J Virol / Year: 2021
Title: Structures of Foot-and-Mouth Disease Virus with Bovine Neutralizing Antibodies Reveal the Determinant of Intraserotype Cross-Neutralization.
Authors: Yong He / Kun Li / Li Wang / Zixian Sun / Yimei Cao / Pinghua Li / Pu Sun / Huifang Bao / Shasha Zhou / Sheng Wang / Xingwen Bai / Xuerong Liu / Lixia Zhao / Xiuli Fan / Zaixin Liu / Zengjun ...Authors: Yong He / Kun Li / Li Wang / Zixian Sun / Yimei Cao / Pinghua Li / Pu Sun / Huifang Bao / Shasha Zhou / Sheng Wang / Xingwen Bai / Xuerong Liu / Lixia Zhao / Xiuli Fan / Zaixin Liu / Zengjun Lu / Cheng Yang / Zhiyong Lou /
Abstract: Foot-and-mouth disease virus (FMDV) exhibits broad antigenic diversity with poor intraserotype cross-neutralizing activity. Studies of the determinant involved in this diversity are essential for the ...Foot-and-mouth disease virus (FMDV) exhibits broad antigenic diversity with poor intraserotype cross-neutralizing activity. Studies of the determinant involved in this diversity are essential for the development of broadly protective vaccines. In this work, we isolated a bovine antibody, designated R55, that displays cross-reaction with both FMDV A/AF/72 (hereafter named FMDV-AAF) and FMDV A/WH/09 (hereafter named FMDV-AWH) but only has a neutralizing effect on FMDV-AWH. Near-atomic resolution structures of FMDV-AAF-R55 and FMDV-AWH-R55 show that R55 engages the capsids of both FMDV-AAF and FMDV-AWH near the icosahedral 3-fold axis and binds to the βB and BC/HI-loops of VP2 and to the B-B knob of VP3. The common interaction residues are highly conserved, which is the major determinant for cross-reaction with both FMDV-AAF and FMDV-AWH. In addition, the cryo-EM structure of the FMDV-AWH-R55 complex also shows that R55 binds to E70 located at the VP3 BC-loop in an adjacent pentamer, which enhances the acid and thermal stabilities of the viral capsid. This may prevent capsid dissociation and genome release into host cells, eventually leading to neutralization of the viral infection. In contrast, R55 binds only to the FMDV-AAF capsid within one pentamer due to the E70G variation, which neither enhances capsid stability nor neutralizes FMDV-AAF infection. The E70G mutation is the major determinant involved in the neutralizing differences between FMDV-AWH and FMDV-AAF. The crucial amino acid E70 is a key component of the neutralizing epitopes, which may aid in the development of broadly protective vaccines. Foot-and-mouth disease virus (FMDV) causes a highly contagious and economically devastating disease in cloven-hoofed animals, and neutralizing antibodies play critical roles in the defense against viral infections. Here, we isolated a bovine antibody (R55) using the single B cell antibody isolation technique. Enzyme-linked immunosorbent assays (ELISA) and virus neutralization tests (VNT) showed that R55 displays cross-reactions with both FMDV-AWH and FMDV-AAF but only has a neutralizing effect on FMDV-AWH. Cryo-EM structures, fluorescence-based thermal stability assays and acid stability assays showed that R55 engages the capsid of FMDV-AWH near the icosahedral 3-fold axis and informs an interpentamer epitope, which overstabilizes virions to hinder capsid dissociation to release the genome, eventually leading to neutralization of viral infection. The crucial amino acid E70 forms a key component of neutralizing epitopes, and the determination of the E70G mutation involved in the neutralizing differences between FMDV-AWH and FMDV-AAF could aid in the development of broadly protective vaccines.
History
DepositionJul 20, 2021Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Sep 29, 2021Provider: repository / Type: Initial release
Revision 1.1Oct 13, 2021Group: Database references / Structure summary / Category: audit_author / citation / citation_author
Item: _audit_author.name / _citation.country ..._audit_author.name / _citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Feb 16, 2022Group: Database references / Derived calculations / Category: citation / pdbx_struct_oper_list
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _pdbx_struct_oper_list.name / _pdbx_struct_oper_list.symmetry_operation / _pdbx_struct_oper_list.type

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Structure visualization

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  • Biological unit as complete icosahedral assembly
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  • Biological unit as icosahedral pentamer
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  • Biological unit as icosahedral 23 hexamer
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  • Deposited structure unit
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  • Simplified surface model + fitted atomic model
  • EMDB-31555
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  • Superimposition on EM map
  • EMDB-31555
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Structure viewerMolecule:
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Assembly

Deposited unit
1: Capsid protein VP0
2: Capsid protein VP0
3: Capsid protein VP0
4: Capsid protein VP0
H: IG HEAVY CHAIN VARIABLE REGION
L: IG LAMDA CHAIN VARIABLE REGION


Theoretical massNumber of molelcules
Total (without water)107,3816
Polymers107,3816
Non-polymers00
Water0
1
1: Capsid protein VP0
2: Capsid protein VP0
3: Capsid protein VP0
4: Capsid protein VP0
H: IG HEAVY CHAIN VARIABLE REGION
L: IG LAMDA CHAIN VARIABLE REGION
x 60


Theoretical massNumber of molelcules
Total (without water)6,442,885360
Polymers6,442,885360
Non-polymers00
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
point symmetry operation59
2


  • Idetical with deposited unit
  • icosahedral asymmetric unit
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
1: Capsid protein VP0
2: Capsid protein VP0
3: Capsid protein VP0
4: Capsid protein VP0
H: IG HEAVY CHAIN VARIABLE REGION
L: IG LAMDA CHAIN VARIABLE REGION
x 5


  • icosahedral pentamer
  • 537 kDa, 30 polymers
Theoretical massNumber of molelcules
Total (without water)536,90730
Polymers536,90730
Non-polymers00
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
point symmetry operation4
4
1: Capsid protein VP0
2: Capsid protein VP0
3: Capsid protein VP0
4: Capsid protein VP0
H: IG HEAVY CHAIN VARIABLE REGION
L: IG LAMDA CHAIN VARIABLE REGION
x 6


  • icosahedral 23 hexamer
  • 644 kDa, 36 polymers
Theoretical massNumber of molelcules
Total (without water)644,28936
Polymers644,28936
Non-polymers00
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
point symmetry operation5
5


  • Idetical with deposited unit in distinct coordinate
  • icosahedral asymmetric unit, std point frame
TypeNameSymmetry operationNumber
transform to point frame1
SymmetryPoint symmetry: (Schoenflies symbol: I (icosahedral))

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Components

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Capsid protein ... , 4 types, 4 molecules 1234

#1: Protein Capsid protein VP0 / / A/WH/CHA/09 VP1 / Capsid protein VP1 / Capsid protein VP3 / Genome polyprotein / P1C / P1D / Virion ...A/WH/CHA/09 VP1 / Capsid protein VP1 / Capsid protein VP3 / Genome polyprotein / P1C / P1D / Virion protein 1 / Virion protein 3


Mass: 23402.678 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Foot-and-mouth disease virus - type A / References: UniProt: E7D639
#2: Protein Capsid protein VP0 / / A/WH/CHA/09 VP2 / Capsid protein VP1 / Capsid protein VP3 / Genome polyprotein / P1C / P1D / Virion ...A/WH/CHA/09 VP2 / Capsid protein VP1 / Capsid protein VP3 / Genome polyprotein / P1C / P1D / Virion protein 1 / Virion protein 3


Mass: 24541.584 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Foot-and-mouth disease virus - type A
References: UniProt: J9PFK1, RNA-directed RNA polymerase, nucleoside-triphosphate phosphatase
#3: Protein Capsid protein VP0 / / A/WH/CHA/09 VP3 / Capsid protein VP1 / Capsid protein VP3 / Genome polyprotein / P1C / P1D / Virion ...A/WH/CHA/09 VP3 / Capsid protein VP1 / Capsid protein VP3 / Genome polyprotein / P1C / P1D / Virion protein 1 / Virion protein 3


Mass: 24157.025 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Foot-and-mouth disease virus - type A / References: UniProt: U5JG68
#4: Protein Capsid protein VP0 / / A/WH/CHA/09 VP4 / VP4-VP2


Mass: 8778.129 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Foot-and-mouth disease virus - type A / References: UniProt: P03309

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Antibody , 2 types, 2 molecules HL

#5: Antibody IG HEAVY CHAIN VARIABLE REGION


Mass: 13615.155 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Bos taurus (cattle) / Production host: Escherichia coli BL21 (bacteria)
#6: Antibody IG LAMDA CHAIN VARIABLE REGION


Mass: 12886.850 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Bos taurus (cattle) / Production host: Escherichia coli BL21 (bacteria)

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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
IDNameTypeEntity IDParent-IDSource
1Complex of FMDV A/WH/CHA/09 and bovine neutralizing scFv antibody R55COMPLEXall0MULTIPLE SOURCES
2FMDV A/WH/CHA/09COMPLEX#1-#41NATURAL
3bovine neutralizing scFv antibody R55COMPLEX#5-#61RECOMBINANT
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
21Foot-and-mouth disease virus - type A12111
32Bos taurus (cattle)9913
Source (recombinant)Organism: Escherichia coli BL21 (bacteria)
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company
MicroscopyModel: FEI TALOS ARCTICA
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy
Image recordingElectron dose: 25 e/Å2 / Film or detector model: DIRECT ELECTRON DE-16 (4k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.91 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 14535 / Symmetry type: POINT

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