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- PDB-7x37: Cryo-EM structure of Coxsackievirus B1 A particle in complex with... -

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Basic information

Entry
Database: PDB / ID: 7x37
TitleCryo-EM structure of Coxsackievirus B1 A particle in complex with nAb 2E6 (CVB1-A:2E6)
Components
  • 2E6 heavy chain
  • 2E6 light chain
  • VP2
  • VP3
  • Virion protein 1
KeywordsVIRUS / Coxsackievirus B1 / Neutralizing antibody / Cryo-EM
Function / homology
Function and homology information


symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of RIG-I activity / picornain 2A / symbiont-mediated suppression of host mRNA export from nucleus / symbiont genome entry into host cell via pore formation in plasma membrane / picornain 3C / T=pseudo3 icosahedral viral capsid / RNA-protein covalent cross-linking / cytoplasmic vesicle membrane / host cell cytoplasmic vesicle membrane / viral capsid ...symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of RIG-I activity / picornain 2A / symbiont-mediated suppression of host mRNA export from nucleus / symbiont genome entry into host cell via pore formation in plasma membrane / picornain 3C / T=pseudo3 icosahedral viral capsid / RNA-protein covalent cross-linking / cytoplasmic vesicle membrane / host cell cytoplasmic vesicle membrane / viral capsid / nucleoside-triphosphate phosphatase / channel activity / monoatomic ion transmembrane transport / DNA replication / RNA helicase activity / endocytosis involved in viral entry into host cell / symbiont-mediated activation of host autophagy / symbiont entry into host cell / RNA-directed RNA polymerase / cysteine-type endopeptidase activity / viral RNA genome replication / RNA-directed RNA polymerase activity / : / DNA-templated transcription / host cell nucleus / virion attachment to host cell / structural molecule activity / ATP hydrolysis activity / proteolysis / RNA binding / ATP binding / metal ion binding
Similarity search - Function
Picornavirus coat protein VP4 superfamily / Poliovirus 3A protein-like / Poliovirus 3A protein like / Picornavirus 2B protein / Poliovirus core protein 3a, soluble domain / Picornavirus 2B protein / Peptidase C3, picornavirus core protein 2A / Picornavirus core protein 2A / Picornavirus coat protein VP4 / Picornavirus coat protein (VP4) ...Picornavirus coat protein VP4 superfamily / Poliovirus 3A protein-like / Poliovirus 3A protein like / Picornavirus 2B protein / Poliovirus core protein 3a, soluble domain / Picornavirus 2B protein / Peptidase C3, picornavirus core protein 2A / Picornavirus core protein 2A / Picornavirus coat protein VP4 / Picornavirus coat protein (VP4) / 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. / ATPases associated with a variety of cellular activities / AAA+ ATPase domain / 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 / Genome polyprotein
Similarity search - Component
Biological speciesMus musculus (house mouse)
Coxsackievirus B1
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.31 Å
AuthorsZheng, Q. / Zhu, R. / Sun, H. / Cheng, T. / Li, S. / Xia, N.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Cell Host Microbe / Year: 2022
Title: Structural basis for the synergistic neutralization of coxsackievirus B1 by a triple-antibody cocktail.
Authors: Qingbing Zheng / Rui Zhu / Zhichao Yin / Longfa Xu / Hui Sun / Hai Yu / Yuanyuan Wu / Yichao Jiang / Qiongzi Huang / Yang Huang / Dongqing Zhang / Liqin Liu / Hongwei Yang / Maozhou He / ...Authors: Qingbing Zheng / Rui Zhu / Zhichao Yin / Longfa Xu / Hui Sun / Hai Yu / Yuanyuan Wu / Yichao Jiang / Qiongzi Huang / Yang Huang / Dongqing Zhang / Liqin Liu / Hongwei Yang / Maozhou He / Zhenhong Zhou / Yanan Jiang / Zhenqin Chen / Huan Zhao / Yuqiong Que / Zhibo Kong / Lizhi Zhou / Tingting Li / Jun Zhang / Wenxin Luo / Ying Gu / Tong Cheng / Shaowei Li / Ningshao Xia /
Abstract: Coxsackievirus B1 (CVB1) is an emerging pathogen associated with severe neonatal diseases including aseptic meningitis, myocarditis, and pancreatitis and also with the development of type 1 diabetes. ...Coxsackievirus B1 (CVB1) is an emerging pathogen associated with severe neonatal diseases including aseptic meningitis, myocarditis, and pancreatitis and also with the development of type 1 diabetes. We characterize the binding and therapeutic efficacies of three CVB1-specific neutralizing antibodies (nAbs) identified for their ability to inhibit host receptor engagement. High-resolution cryo-EM structures showed that these antibodies recognize different epitopes but with an overlapping region in the capsid VP2 protein and specifically the highly variable EF loop. Moreover, they perturb capsid-receptor interactions by binding various viral particle forms. Antibody combinations achieve synergetic neutralization via a stepwise capsid transition and virion disruption, indicating dynamic changes in the virion in response to multiple nAbs targeting the receptor-binding site. Furthermore, this three-antibody cocktail protects against lethal challenge in neonatal mice and limits pancreatitis and viral replication in a non-obese diabetic mouse model. These results illustrate the utility of nAbs for rational design of therapeutics against picornaviruses such as CVB.
History
DepositionFeb 28, 2022Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Sep 28, 2022Provider: repository / Type: Initial release
Revision 1.1Oct 5, 2022Group: Database references / Category: citation / Item: _citation.journal_volume / _citation.page_first
Revision 1.2Oct 9, 2024Group: Data collection / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
L: 2E6 light chain
H: 2E6 heavy chain
A: Virion protein 1
B: VP2
C: VP3


Theoretical massNumber of molelcules
Total (without water)111,4705
Polymers111,4705
Non-polymers00
Water00
1
L: 2E6 light chain
H: 2E6 heavy chain
A: Virion protein 1
B: VP2
C: VP3
x 60


Theoretical massNumber of molelcules
Total (without water)6,688,213300
Polymers6,688,213300
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: 2E6 light chain
H: 2E6 heavy chain
A: Virion protein 1
B: VP2
C: VP3
x 5


  • icosahedral pentamer
  • 557 kDa, 25 polymers
Theoretical massNumber of molelcules
Total (without water)557,35125
Polymers557,35125
Non-polymers00
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
point symmetry operation4
4
L: 2E6 light chain
H: 2E6 heavy chain
A: Virion protein 1
B: VP2
C: VP3
x 6


  • icosahedral 23 hexamer
  • 669 kDa, 30 polymers
Theoretical massNumber of molelcules
Total (without water)668,82130
Polymers668,82130
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 2E6 light chain


Mass: 11720.020 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Mus musculus (house mouse)
#2: Antibody 2E6 heavy chain


Mass: 13091.568 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Mus musculus (house mouse)
#3: Protein Virion protein 1 / VP1 / P1C / P1D


Mass: 31207.117 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Coxsackievirus B1 / References: UniProt: W8GTF7
#4: Protein VP2


Mass: 29122.744 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Coxsackievirus B1 / References: UniProt: A0A2S0RQC2
#5: Protein VP3


Mass: 26328.764 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Coxsackievirus B1
References: UniProt: L7UV52, picornain 2A, nucleoside-triphosphate phosphatase, picornain 3C, RNA-directed RNA polymerase
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

ComponentName: Cryo-EM structure of Coxsackievirus B1 A particle in complex with nAb 2E6 (CVB1-A:2E6)
Type: COMPLEX / Entity ID: all / Source: NATURAL
Source (natural)Organism: Coxsackievirus B1
Source (recombinant)Organism: Cricetulus griseus (Chinese hamster)
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: Tecnai F30 / Image courtesy: FEI Company
MicroscopyModel: FEI TECNAI F30
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 3500 nm / Nominal defocus min: 1200 nm
Image recordingElectron dose: 60 e/Å2 / Detector mode: INTEGRATING / Film or detector model: FEI FALCON III (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.14_3259: / Classification: refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.31 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 36573 / Symmetry type: POINT

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