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- PDB-6l62: Neutralization mechanism of a monoclonal antibody targeting a por... -

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Basic information

Entry
Database: PDB / ID: 6l62
TitleNeutralization mechanism of a monoclonal antibody targeting a porcine circovirus type 2 Cap protein conformational epitope
Components
  • Capsid protein
  • Heavy chain of Fab fragment
  • Light chain of Fab fragment
KeywordsIMMUNE SYSTEM/VIRUS / Porcine circovirus type 2 / Cap protein / VIRUS / IMMUNE SYSTEM-VIRUS complex
Function / homologyCircovirus capsid protein / Circovirus capsid superfamily / Circovirus capsid protein / viral capsid assembly / T=1 icosahedral viral capsid / symbiont entry into host cell / virion attachment to host cell / Capsid protein
Function and homology information
Biological speciesMus musculus (house mouse)
Porcine circovirus 2
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 7.2 Å
AuthorsSun, Z. / Huang, L. / Xia, D. / Wei, Y. / Sun, E. / Zhu, H. / Bian, H. / Wu, H. / Feng, L. / Wang, J. / Liu, C.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)31873012 China
CitationJournal: J Virol / Year: 2020
Title: Neutralization Mechanism of a Monoclonal Antibody Targeting a Porcine Circovirus Type 2 Cap Protein Conformational Epitope.
Authors: Liping Huang / Zhenzhao Sun / Deli Xia / Yanwu Wei / Encheng Sun / Chunguo Liu / Hongzhen Zhu / Haiqiao Bian / Hongli Wu / Li Feng / Jingfei Wang / Changming Liu /
Abstract: Porcine circovirus type 2 (PCV2) is an important pathogen in swine herds, and its infection of pigs has caused severe economic losses to the pig industry worldwide. The capsid protein of PCV2 is the ...Porcine circovirus type 2 (PCV2) is an important pathogen in swine herds, and its infection of pigs has caused severe economic losses to the pig industry worldwide. The capsid protein of PCV2 is the only structural protein that is associated with PCV2 infection and immunity. Here, we report a neutralizing monoclonal antibody (MAb), MAb 3A5, that binds to intact PCV2 virions of the PCV2a, PCV2b, and PCV2d genotypes. MAb 3A5 neutralized PCV2 by blocking viral attachment to PK15 cells. To further explore the neutralization mechanism, we resolved the structure of the PCV2 virion in complex with MAb 3A5 Fab fragments by using cryo-electron microscopy single-particle analysis. The binding sites were located at the topmost edges around 5-fold icosahedral symmetry axes, with each footprint covering amino acids from two adjacent capsid proteins. Most of the epitope residues (15/18 residues) were conserved among 2,273 PCV2 strains. Mutations of some amino acids within the epitope had significant effects on the neutralizing activity of MAb 3A5. This study reveals the molecular and structural bases of this PCV2-neutralizing antibody and provides new and important information for vaccine design and therapeutic antibody development against PCV2 infections. PCV2 is associated with several clinical manifestations collectively known as PCV2-associated diseases (PCVADs). Neutralizing antibodies play a crucial role in the prevention of PCVADs. We demonstrated previously that a MAb, MAb 3A5, neutralizes the PCV2a, PCV2b, and PCV2d genotypes with different degrees of efficiency, but the underlying mechanism remains elusive. Here, we report the neutralization mechanism of this MAb and the structure of the PCV2 virion in complex with MAb 3A5 Fabs, showing a binding mode in which one Fab interacted with more than two loops from two adjacent capsid proteins. This binding mode has not been observed previously for PCV2-neutralizing antibodies. Our work provides new and important information for vaccine design and therapeutic antibody development against PCV2 infections.
History
DepositionOct 25, 2019Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Feb 12, 2020Provider: repository / Type: Initial release
Revision 1.1Mar 4, 2020Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Apr 29, 2020Group: Database references / Category: citation / Item: _citation.journal_volume
Revision 1.3Nov 20, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / em_admin / pdbx_entry_details / pdbx_modification_feature / pdbx_struct_oper_list
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _em_admin.last_update / _pdbx_struct_oper_list.name / _pdbx_struct_oper_list.symmetry_operation / _pdbx_struct_oper_list.type

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Structure visualization

Movie
  • 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-0838
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  • Superimposition on EM map
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Structure viewerMolecule:
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Assembly

Deposited unit
L: Light chain of Fab fragment
H: Heavy chain of Fab fragment
A: Capsid protein


Theoretical massNumber of molelcules
Total (without water)74,8523
Polymers74,8523
Non-polymers00
Water00
1
L: Light chain of Fab fragment
H: Heavy chain of Fab fragment
A: Capsid protein
x 60


Theoretical massNumber of molelcules
Total (without water)4,491,124180
Polymers4,491,124180
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
L: Light chain of Fab fragment
H: Heavy chain of Fab fragment
A: Capsid protein
x 5


  • icosahedral pentamer
  • 374 kDa, 15 polymers
Theoretical massNumber of molelcules
Total (without water)374,26015
Polymers374,26015
Non-polymers00
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
point symmetry operation4
4
L: Light chain of Fab fragment
H: Heavy chain of Fab fragment
A: Capsid protein
x 6


  • icosahedral 23 hexamer
  • 449 kDa, 18 polymers
Theoretical massNumber of molelcules
Total (without water)449,11218
Polymers449,11218
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

#1: Antibody Light chain of Fab fragment


Mass: 23564.074 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Mus musculus (house mouse)
#2: Antibody Heavy chain of Fab fragment


Mass: 23728.473 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Mus musculus (house mouse)
#3: Protein Capsid protein


Mass: 27559.520 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Porcine circovirus 2 / References: UniProt: F5A4Z4
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
1PCV2 virion in complex with Fab fragments of the mAb 3A5COMPLEXall0NATURAL
2Light chain of Fab fragment of the mAb 3A5COMPLEX#11NATURAL
3Heavy chain of Fab fragment Fab of the mAb 3A5COMPLEX#21NATURAL
4PCV2 virionCOMPLEX#31NATURAL
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
21Mus musculus (house mouse)10090
32Mus musculus (house mouse)10090
43mus muscu (virus)85708
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 FIELD
Image recording
IDImaging-IDElectron dose (e/Å2)Film or detector model
1135FEI CETA (4k x 4k)
2135FEI CETA (4k x 4k)
3135FEI CETA (4k x 4k)

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Processing

CTF correctionType: NONE
3D reconstructionResolution: 7.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 3500 / Symmetry type: POINT

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