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- PDB-5zuf: Fit R10 Fab coordinates into the cryo-EM of EV71 in complex with A9 -

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Basic information

Entry
Database: PDB / ID: 5zuf
TitleFit R10 Fab coordinates into the cryo-EM of EV71 in complex with A9
Components
  • Capsid protein VP1
  • R10 ANTIBODY HEAVY CHAIN
  • R10 ANTIBODY LIGHT CHAIN
  • VP2
  • VP3
KeywordsVIRUS LIKE PARTICLE / EV71 neutralizing Fab / A9 antibody
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 / symbiont-mediated suppression of host gene expression ...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 / symbiont-mediated suppression of host gene expression / nucleoside-triphosphate phosphatase / channel activity / viral capsid / monoatomic ion transmembrane transport / RNA helicase activity / 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 / 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
Genome polyprotein / Genome polyprotein / Genome polyprotein / Genome polyprotein
Similarity search - Component
Biological speciesEnterovirus A71
Mus musculoides (Temminck's mouse)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 6.8 Å
AuthorsWang, X. / Zhu, L. / Wang, N.
CitationJournal: mBio / Year: 2018
Title: Neutralization Mechanisms of Two Highly Potent Antibodies against Human Enterovirus 71.
Authors: Ling Zhu / Kangwei Xu / Nan Wang / Lei Cao / Junlan Wu / Qiang Gao / Elizabeth E Fry / David I Stuart / Zihe Rao / Junzhi Wang / Xiangxi Wang /
Abstract: Despite significant advances in health care, outbreaks of infections by enteroviruses (EVs) continue to plague the Asia-Pacific region every year. Enterovirus 71 (EV71) causes hand-foot-and-mouth ...Despite significant advances in health care, outbreaks of infections by enteroviruses (EVs) continue to plague the Asia-Pacific region every year. Enterovirus 71 (EV71) causes hand-foot-and-mouth disease (HFMD), for which there are currently no therapeutics. Here, we report two new antibodies, A9 and D6, that potently neutralize EV71. A9 exhibited a 50% neutralizing concentration (neut) value of 0.1 nM against EV71, which was 10-fold lower than that observed for D6. Investigation into the mechanisms of neutralization revealed that binding of A9 to EV71 blocks receptor binding but also destabilizes and damages the virus capsid structure. In contrast, D6 destabilizes the capsid only slightly but interferes more potently with the attachment of the virus to the host cells. Cryo-electron microscopy (cryo-EM) structures of A9 and D6 bound with EV71 shed light on the locations and nature of the epitopes recognized by the two antibodies. Although some regions of the epitopes recognized by the two antibodies overlap, there are differences that give rise to dissimilarities in potency as well as in the mechanisms of neutralization. Interestingly, the overlapping regions of the epitopes encompass the site that the virus uses to bind SCARB2, explaining the reason for the observed blocking of the virus-receptor interaction by the two antibodies. We also identified structural elements that might play roles in modulating the stability of the EV71 particles, including particle integrity. The molecular features of the A9 and D6 epitopes unveiled in this study open up new avenues for rationally designing antiviral drugs. During the course of viral infections, the human body produces neutralizing antibodies which play a defining role in clearing the virus. From this study, we report two new, highly potent neutralizing antibodies, A9 and D6, against enterovirus 71 (EV71), the causative agent of HFMD. Both antibodies prevent the virus from entering the host cell, a step that is important for establishing a successful infection. A9 destabilizes and damages the virus capsid that forms an outer protective covering around the genome of the virus, while also interfering with virus attachment to the host cells. In contrast, D6 only prevents binding of the virus to its receptor(s). The mechanism of neutralization of A9 is unique and has not been observed before for neutralizing antibodies targeting EVs. The two antibodies that we are reporting in this study have potential to be developed into much-needed therapeutic interventions for treatment of HFMD, outbreaks of which are reported every year in the Asia-Pacific region.
History
DepositionMay 7, 2018Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Dec 25, 2019Provider: repository / Type: Initial release
Revision 1.1Jan 6, 2021Group: 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.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Sep 25, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Source and taxonomy
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / em_admin / em_entity_assembly_recombinant / 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 / _em_entity_assembly_recombinant.id / _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
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  • Superimposition on EM map
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Structure viewerMolecule:
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Assembly

Deposited unit
A: Capsid protein VP1
B: VP2
C: VP3
D: R10 ANTIBODY LIGHT CHAIN
E: R10 ANTIBODY HEAVY CHAIN


Theoretical massNumber of molelcules
Total (without water)133,0865
Polymers133,0865
Non-polymers00
Water00
1
A: Capsid protein VP1
B: VP2
C: VP3
D: R10 ANTIBODY LIGHT CHAIN
E: R10 ANTIBODY HEAVY CHAIN
x 60


Theoretical massNumber of molelcules
Total (without water)7,985,134300
Polymers7,985,134300
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
A: Capsid protein VP1
B: VP2
C: VP3
D: R10 ANTIBODY LIGHT CHAIN
E: R10 ANTIBODY HEAVY CHAIN
x 5


  • icosahedral pentamer
  • 665 kDa, 25 polymers
Theoretical massNumber of molelcules
Total (without water)665,42825
Polymers665,42825
Non-polymers00
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
point symmetry operation4
4
A: Capsid protein VP1
B: VP2
C: VP3
D: R10 ANTIBODY LIGHT CHAIN
E: R10 ANTIBODY HEAVY CHAIN
x 6


  • icosahedral 23 hexamer
  • 799 kDa, 30 polymers
Theoretical massNumber of molelcules
Total (without water)798,51330
Polymers798,51330
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: Protein Capsid protein VP1


Mass: 32787.902 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Enterovirus A71 / Cell line (production host): VERO / Production host: Chlorocebus aethiops (grivet) / References: UniProt: G5CUH3
#2: Protein VP2


Mass: 26874.252 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Enterovirus A71 / Cell line (production host): VERO / Production host: Chlorocebus aethiops (grivet) / References: UniProt: A0A1P8LK26, UniProt: E0WWC7*PLUS
#3: Protein VP3


Mass: 26468.225 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Enterovirus A71 / Cell line (production host): VERO / Production host: Chlorocebus aethiops (grivet) / References: UniProt: W8XVT2
#4: Antibody R10 ANTIBODY LIGHT CHAIN


Mass: 23283.535 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculoides (Temminck's mouse) / Cell line (production host): BONE MARROW HYBRIDOMA CELL / Production host: Mus musculoides (Temminck's mouse)
#5: Antibody R10 ANTIBODY HEAVY CHAIN


Mass: 23671.650 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculoides (Temminck's mouse) / Cell line (production host): BONE MARROW HYBRIDOMA CELL / Production host: Mus musculoides (Temminck's mouse)

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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 EV71 and A9 neutralizing antibody FabCOMPLEXall0RECOMBINANT
2EV71COMPLEX#1-#31RECOMBINANT
3A9 neutralizing antibody FabCOMPLEX#4-#51RECOMBINANT
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
12Enterovirus A7139054
23Mus musculoides (Temminck's mouse)60742
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
12Chlorocebus aethiops (grivet)9534
23Mus musculoides (Temminck's mouse)60742
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 Polara / Image courtesy: FEI Company
MicroscopyModel: FEI POLARA 300
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD
Image recordingElectron dose: 20 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

CTF correctionType: NONE
3D reconstructionResolution: 6.8 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 1100 / Symmetry type: POINT

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