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- PDB-8y0r: Complex of FMDV A/WH/CHA/09 and inter-serotype broadly neutralizi... -

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Basic information

Entry
Database: PDB / ID: 8y0r
TitleComplex of FMDV A/WH/CHA/09 and inter-serotype broadly neutralizing antibodies pOA-2
Components
  • VP1 of capsid protein
  • VP2 of capsid protein
  • VP3 of capsid protein
  • VP4 of capsid protein
  • pOA2 VH
  • pOA2 VL
KeywordsVIRUS/IMMUNE SYSTEM / Foot-and-mouth disease virus A / Sus scrofa / VIRUS-IMMUNE SYSTEM complex
Function / homology
Function and homology information


symbiont-mediated perturbation of host chromatin organization / ribonucleoside triphosphate phosphatase activity / T=pseudo3 icosahedral viral capsid / host cell cytoplasmic vesicle membrane / regulation of translation / channel activity / monoatomic ion transmembrane transport / clathrin-dependent endocytosis of virus by host cell / RNA helicase activity / viral protein processing ...symbiont-mediated perturbation of host chromatin organization / ribonucleoside triphosphate phosphatase activity / T=pseudo3 icosahedral viral capsid / host cell cytoplasmic vesicle membrane / regulation of translation / channel activity / monoatomic ion transmembrane transport / clathrin-dependent endocytosis of virus by host cell / RNA helicase activity / viral protein processing / host cell endoplasmic reticulum membrane / cysteine-type endopeptidase activity / viral RNA genome replication / RNA-directed RNA polymerase activity / DNA-templated transcription / virion attachment to host cell / host cell nucleus / structural molecule activity / proteolysis / RNA binding / ATP binding / membrane
Similarity search - Function
Peptidase C28, foot-and-mouth virus L-proteinase / Foot-and-mouth virus L-proteinase / Aphthovirus leader protease (L(pro)) domain profile. / 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 / Picornavirus coat protein / Papain-like cysteine peptidase superfamily ...Peptidase C28, foot-and-mouth virus L-proteinase / Foot-and-mouth virus L-proteinase / Aphthovirus leader protease (L(pro)) domain profile. / 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 / Picornavirus coat protein / Papain-like cysteine peptidase superfamily / Peptidase C3A/C3B, picornaviral / 3C cysteine protease (picornain 3C) / Picornavirales 3C/3C-like protease domain / Picornavirales 3C/3C-like protease domain profile. / 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 / 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
Genome polyprotein / Genome polyprotein
Similarity search - Component
Biological speciesSus scrofa (pig)
Foot-and-mouth disease virus A
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.52 Å
AuthorsWu, S. / Lei, D.
Funding support China, 6items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)32373028 China
National Natural Science Foundation of China (NSFC)32171300 China
National Natural Science Foundation of China (NSFC)32072873 China
Other government2021YFD1800304 China
Other governmentlzujbky-2021-ct05 China
Other governmentNCTIP-MY23004 China
CitationJournal: PLoS Pathog / Year: 2024
Title: Discovery, recognized antigenic structures, and evolution of cross-serotype broadly neutralizing antibodies from porcine B-cell repertoires against foot-and-mouth disease virus.
Authors: Fengjuan Li / Shanquan Wu / Lv Lv / Shulun Huang / Zelin Zhang / Zhaxi Zerang / Pinghua Li / Yimei Cao / Huifang Bao / Pu Sun / Xingwen Bai / Yong He / Yuanfang Fu / Hong Yuan / Xueqing Ma / ...Authors: Fengjuan Li / Shanquan Wu / Lv Lv / Shulun Huang / Zelin Zhang / Zhaxi Zerang / Pinghua Li / Yimei Cao / Huifang Bao / Pu Sun / Xingwen Bai / Yong He / Yuanfang Fu / Hong Yuan / Xueqing Ma / Zhixun Zhao / Jing Zhang / Jian Wang / Tao Wang / Dong Li / Qiang Zhang / Jijun He / Zaixin Liu / Zengjun Lu / Dongsheng Lei / Kun Li /
Abstract: It is a great challenge to isolate the broadly neutralizing antibodies (bnAbs) against foot-and-mouth disease virus (FMDV) due to its existence as seven distinct serotypes without cross-protection. ...It is a great challenge to isolate the broadly neutralizing antibodies (bnAbs) against foot-and-mouth disease virus (FMDV) due to its existence as seven distinct serotypes without cross-protection. Here, by vaccination of pig with FMDV serotypes O and A whole virus antigens, we obtained 10 bnAbs against serotypes O, A and/or Asia1 by dissecting 216 common clonotypes of two serotypes O and A specific porcine B-cell receptor (BCR) gene repertoires containing total 12720 B cell clones, indicating the induction of cross-serotype bnAbs after sequential vaccination with serotypes O and A antigens. The majority of porcine bnAbs (9/10) were derived from terminally differentiated B cells of different clonal lineages, which convergently targeted the conserved "RGDL" motif on structural protein VP1 of FMDV by mimicking receptor recognition to inhibit viral attachment to cells. Cryo-EM complex structures revealed that the other bnAb pOA-2 specifically targets a novel inter-pentamer antigen structure surrounding the viral three-fold axis, with a highly conserved determinant at residue 68 on VP2. This unique binding pattern enabled cross-serotype neutralization by destabilizing the viral particle. The evolutionary analysis of pOA-2 demonstrated its origin from an intermediate B-cell, emphasizing the crucial role of somatic hypermutations (SHMs) in balancing the breadth and potency of neutralization. However, excessive SHMs may deviate from the trajectory of broad neutralization. This study provides a strategy to uncover bnAbs against highly mutable pathogens and the cross-serotype antigenic structures to explore broadly protective FMDV vaccine.
History
DepositionJan 23, 2024Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Oct 9, 2024Provider: repository / Type: Initial release
Revision 1.1Nov 13, 2024Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
1: VP1 of capsid protein
2: VP2 of capsid protein
3: VP3 of capsid protein
4: VP4 of capsid protein
H: pOA2 VH
L: pOA2 VL


Theoretical massNumber of molelcules
Total (without water)106,1896
Polymers106,1896
Non-polymers00
Water00
1
1: VP1 of capsid protein
2: VP2 of capsid protein
3: VP3 of capsid protein
4: VP4 of capsid protein
H: pOA2 VH
L: pOA2 VL
x 60


Theoretical massNumber of molelcules
Total (without water)6,371,325360
Polymers6,371,325360
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: VP1 of capsid protein
2: VP2 of capsid protein
3: VP3 of capsid protein
4: VP4 of capsid protein
H: pOA2 VH
L: pOA2 VL
x 5


  • icosahedral pentamer
  • 531 kDa, 30 polymers
Theoretical massNumber of molelcules
Total (without water)530,94430
Polymers530,94430
Non-polymers00
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
point symmetry operation4
4
1: VP1 of capsid protein
2: VP2 of capsid protein
3: VP3 of capsid protein
4: VP4 of capsid protein
H: pOA2 VH
L: pOA2 VL
x 6


  • icosahedral 23 hexamer
  • 637 kDa, 36 polymers
Theoretical massNumber of molelcules
Total (without water)637,13336
Polymers637,13336
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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Protein , 4 types, 4 molecules 1234

#1: Protein VP1 of capsid protein


Mass: 23402.678 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Foot-and-mouth disease virus A / References: UniProt: D0E7R9
#2: Protein VP2 of capsid protein


Mass: 24541.584 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Foot-and-mouth disease virus A / References: UniProt: D0E7R9
#3: Protein VP3 of capsid protein


Mass: 24157.025 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Foot-and-mouth disease virus A / References: UniProt: D0E7R9
#4: Protein VP4 of capsid protein


Mass: 8778.129 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Foot-and-mouth disease virus A / References: UniProt: E4W502

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Antibody , 2 types, 2 molecules HL

#5: Antibody pOA2 VH


Mass: 13721.396 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Sus scrofa (pig) / Production host: Homo sapiens (human)
#6: Antibody pOA2 VL


Mass: 11587.944 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Sus scrofa (pig) / Production host: Homo sapiens (human)

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Details

Has protein modificationY

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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 inter-serotype broadly neutralizing antibodies pOA-2COMPLEXall0MULTIPLE SOURCES
2FMDV A/WH/CHA/09COMPLEX#1-#41NATURAL
3inter-serotype broadly neutralizing antibodies pOA-2COMPLEX#5-#61RECOMBINANT
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
12Foot-and-mouth disease virus A12111
23Sus scrofa (pig)9823
Details of virus
IDEntity assembly-IDIsolateType
11SEROTYPEVIRUS-LIKE PARTICLE
22
33
Buffer solutionpH: 7.6
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: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 30 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

EM software
IDNameVersionCategory
1cryoSPARC3.3particle selection
4CTFFIND4CTF correction
10cryoSPARC3.3initial Euler assignment
11cryoSPARC3.3final Euler assignment
12cryoSPARC3.3classification
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: I (icosahedral)
3D reconstructionResolution: 2.52 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 7341 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0047176
ELECTRON MICROSCOPYf_angle_d0.5529779
ELECTRON MICROSCOPYf_dihedral_angle_d10.9242560
ELECTRON MICROSCOPYf_chiral_restr0.0431090
ELECTRON MICROSCOPYf_plane_restr0.0051268

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