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- PDB-7yrh: Cryo-EM structure of compact coxsackievirus A16 empty particle in... -

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Basic information

Entry
Database: PDB / ID: 7yrh
TitleCryo-EM structure of compact coxsackievirus A16 empty particle in complex with a neutralizing antibody 9B5
Components
  • (Capsid protein ...) x 2
  • Genome polyprotein
  • The heavy chain of the antibody 9B5
  • The light chain of the antibody 9B5
KeywordsSTRUCTURAL PROTEIN / coxsackievirus A16 / antibody 9B5 / cryo-EM
Function / homology
Function and homology information


symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of MDA-5 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 / host cell cytoplasmic vesicle membrane / cytoplasmic vesicle membrane / endocytosis involved in viral entry into host cell / nucleoside-triphosphate phosphatase ...symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of MDA-5 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 / host cell cytoplasmic vesicle membrane / cytoplasmic vesicle membrane / endocytosis involved in viral entry into host cell / nucleoside-triphosphate phosphatase / channel activity / monoatomic ion transmembrane transport / RNA helicase activity / induction by virus of host autophagy / RNA-directed RNA polymerase / viral RNA genome replication / cysteine-type endopeptidase activity / RNA-dependent RNA polymerase activity / virus-mediated perturbation of host defense response / 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 / 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 / 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
SPHINGOSINE / Genome polyprotein / Genome polyprotein
Similarity search - Component
Biological speciesCoxsackievirus A16
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.35 Å
AuthorsCong, Y. / Liu, C.X.
Funding support China, 1items
OrganizationGrant numberCountry
Chinese Academy of SciencesXDB29040300 China
CitationJournal: Nat Commun / Year: 2022
Title: Molecular mechanism of antibody neutralization of coxsackievirus A16.
Authors: Chao Zhang / Caixuan Liu / Jinping Shi / Yalei Wang / Cong Xu / Xiaohua Ye / Qingwei Liu / Xue Li / Weihua Qiao / Yannan Yin / Yao Cong / Zhong Huang /
Abstract: Coxsackievirus A16 (CVA16) causes hand, foot and mouth disease in infants and young children. However, no vaccine or anti-viral agent is currently available for CVA16. Here, the functions and working ...Coxsackievirus A16 (CVA16) causes hand, foot and mouth disease in infants and young children. However, no vaccine or anti-viral agent is currently available for CVA16. Here, the functions and working mechanisms of two CVA16-specific neutralizing monoclonal antibodies (MAbs), 9B5 and 8C4, are comprehensively investigated. Both 9B5 and 8C4 display potent neutralization in vitro and prophylactic and therapeutic efficacy in a mouse model of CVA16 infection. Mechanistically, 9B5 exerts neutralization primarily through inhibiting CVA16 attachment to cell surface via blockade of CVA16 binding to its attachment receptor, heparan sulfate, whereas 8C4 functions mainly at the post-attachment stage of CVA16 entry by interfering with the interaction between CVA16 and its uncoating receptor SCARB2. Cryo-EM studies show that 9B5 and 8C4 target distinct epitopes located at the 5-fold and 3-fold protrusions of CVA16 capsids, respectively, and exhibit differential binding preference to three forms of naturally occurring CVA16 particles. Moreover, 9B5 and 8C4 are compatible in formulating an antibody cocktail which displays the ability to prevent virus escape seen with individual MAbs. Together, our work elucidates the functional and structural basis of CVA16 antibody-mediated neutralization and protection, providing important information for design and development of effective CVA16 vaccines and antibody therapies.
History
DepositionAug 10, 2022Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Sep 14, 2022Provider: repository / Type: Initial release
Revision 1.1Jan 11, 2023Group: Database references / Category: citation / citation_author
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
Revision 1.2Oct 23, 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 / _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Capsid protein VP1
B: Genome polyprotein
C: Capsid protein VP3
E: The light chain of the antibody 9B5
F: The heavy chain of the antibody 9B5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)140,9006
Polymers140,6015
Non-polymers2991
Water00
1
A: Capsid protein VP1
B: Genome polyprotein
C: Capsid protein VP3
E: The light chain of the antibody 9B5
F: The heavy chain of the antibody 9B5
hetero molecules
x 60


Theoretical massNumber of molelcules
Total (without water)8,454,011360
Polymers8,436,042300
Non-polymers17,97060
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
A: Capsid protein VP1
B: Genome polyprotein
C: Capsid protein VP3
E: The light chain of the antibody 9B5
F: The heavy chain of the antibody 9B5
hetero molecules
x 5


  • icosahedral pentamer
  • 705 kDa, 25 polymers
Theoretical massNumber of molelcules
Total (without water)704,50130
Polymers703,00325
Non-polymers1,4975
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
point symmetry operation4
4
A: Capsid protein VP1
B: Genome polyprotein
C: Capsid protein VP3
E: The light chain of the antibody 9B5
F: The heavy chain of the antibody 9B5
hetero molecules
x 6


  • icosahedral 23 hexamer
  • 845 kDa, 30 polymers
Theoretical massNumber of molelcules
Total (without water)845,40136
Polymers843,60430
Non-polymers1,7976
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 ... , 2 types, 2 molecules AC

#1: Protein Capsid protein VP1


Mass: 33080.402 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Coxsackievirus A16 / Production host: Mus sp. (mice)
References: UniProt: M4TAU2, picornain 2A, nucleoside-triphosphate phosphatase, picornain 3C, RNA-directed RNA polymerase
#3: Protein Capsid protein VP3 / VP3


Mass: 26646.318 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Coxsackievirus A16 / Production host: Mus sp. (mice)
References: UniProt: A9LXZ4, picornain 2A, nucleoside-triphosphate phosphatase, picornain 3C, RNA-directed RNA polymerase

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Antibody , 2 types, 2 molecules EF

#4: Antibody The light chain of the antibody 9B5


Mass: 23600.934 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Coxsackievirus A16 / Production host: Cercopithecus (mammal)
#5: Antibody The heavy chain of the antibody 9B5


Mass: 23500.203 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Coxsackievirus A16 / Production host: Cercopithecus (mammal)

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Protein / Non-polymers , 2 types, 2 molecules B

#2: Protein Genome polyprotein


Mass: 33772.840 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Coxsackievirus A16 / Production host: Mus sp. (mice)
References: UniProt: M4TAU2, picornain 2A, nucleoside-triphosphate phosphatase, picornain 3C, RNA-directed RNA polymerase
#6: Chemical ChemComp-SPH / SPHINGOSINE


Mass: 299.492 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H37NO2 / Feature type: SUBJECT OF INVESTIGATION

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Details

Has ligand of interestY
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 compact coxsackievirus A16 empty particle in complex with a neutralizing antibody 9B5
Type: COMPLEX / Entity ID: #1-#5 / Source: RECOMBINANT
Source (natural)Organism: Coxsackievirus A16
Source (recombinant)Organism: Cercopithecus (mammal)
Buffer solutionpH: 7.5
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: 2500 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 38 e/Å2 / Detector mode: SUPER-RESOLUTION / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.35 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 13951 / Symmetry type: POINT

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