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- PDB-7ebr: EV-D68 in complex with 2H12 Fab (state S2) -

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Basic information

Entry
Database: PDB / ID: 7ebr
TitleEV-D68 in complex with 2H12 Fab (state S2)
Components
  • (Capsid protein ...Capsid) x 4
  • 2H12 Fab heavy chain
  • 2H12 Fab light chain
KeywordsVIRUS / Enterovirus D68 / Monoclonal antibody / Uncoating
Function / homology
Function and homology information


: / 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 / : ...: / 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 / protein complex oligomerization / monoatomic ion channel activity / RNA helicase activity / induction by virus of host autophagy / RNA-directed RNA polymerase / symbiont-mediated suppression of host gene expression / viral RNA genome replication / cysteine-type endopeptidase activity / RNA-dependent RNA polymerase activity / DNA-templated transcription / virion attachment to host cell / structural molecule activity / ATP hydrolysis activity / proteolysis / RNA binding / ATP binding / metal ion binding
Similarity search - Function
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) / Picornavirales 3C/3C-like protease domain ...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) / Picornavirales 3C/3C-like protease domain / Picornavirales 3C/3C-like protease domain profile. / Peptidase C3A/C3B, picornaviral / 3C cysteine protease (picornain 3C) / 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
Biological speciesHuman enterovirus D68
Mus musculus (house mouse)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.6 Å
AuthorsXu, C. / Cong, Y.
Funding support China, 1items
OrganizationGrant numberCountry
Chinese Academy of Sciences China
CitationJournal: Nat Commun / Year: 2021
Title: Functional and structural characterization of a two-MAb cocktail for delayed treatment of enterovirus D68 infections.
Authors: Chao Zhang / Cong Xu / Wenlong Dai / Yifan Wang / Zhi Liu / Xueyang Zhang / Xuesong Wang / Haikun Wang / Sitang Gong / Yao Cong / Zhong Huang /
Abstract: Enterovirus D68 (EV-D68) is an emerging pathogen associated with respiratory diseases and/or acute flaccid myelitis. Here, two MAbs, 2H12 and 8F12, raised against EV-D68 virus-like particle (VLP), ...Enterovirus D68 (EV-D68) is an emerging pathogen associated with respiratory diseases and/or acute flaccid myelitis. Here, two MAbs, 2H12 and 8F12, raised against EV-D68 virus-like particle (VLP), show distinct preference in binding VLP and virion and in neutralizing different EV-D68 strains. A combination of 2H12 and 8F12 exhibits balanced and potent neutralization effects and confers broader protection in mice than single MAbs when given at onset of symptoms. Cryo-EM structures of EV-D68 virion complexed with 2H12 or 8F12 show that both antibodies bind to the canyon region of the virion, creating steric hindrance for sialic acid receptor binding. Additionally, 2H12 binding can impair virion integrity and trigger premature viral uncoating. We also capture an uncoating intermediate induced by 2H12 binding, not previously described for picornaviruses. Our study elucidates the structural basis and neutralizing mechanisms of the 2H12 and 8F12 MAbs and supports further development of the 2H12/8F12 cocktail as a broad-spectrum therapeutic agent against EV-D68 infections in humans.
History
DepositionMar 10, 2021Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Mar 31, 2021Provider: repository / Type: Initial release
Revision 1.1Jun 2, 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.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year

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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
  • EMDB-31054
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  • Superimposition on EM map
  • EMDB-31054
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Structure viewerMolecule:
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Assembly

Deposited unit
A: Capsid protein VP1
B: Capsid protein VP3
C: Capsid protein VP2
D: Capsid protein VP4
E: 2H12 Fab heavy chain
F: 2H12 Fab light chain


Theoretical massNumber of molelcules
Total (without water)141,5116
Polymers141,5116
Non-polymers00
Water0
1
A: Capsid protein VP1
B: Capsid protein VP3
C: Capsid protein VP2
D: Capsid protein VP4
E: 2H12 Fab heavy chain
F: 2H12 Fab light chain
x 60


Theoretical massNumber of molelcules
Total (without water)8,490,652360
Polymers8,490,652360
Non-polymers00
Water0
TypeNameSymmetry operationNumber
point symmetry operation60
2


  • Idetical with deposited unit in distinct coordinate
  • icosahedral asymmetric unit
TypeNameSymmetry operationNumber
point symmetry operation1
3
A: Capsid protein VP1
B: Capsid protein VP3
C: Capsid protein VP2
D: Capsid protein VP4
E: 2H12 Fab heavy chain
F: 2H12 Fab light chain
x 5


  • icosahedral pentamer
  • 708 kDa, 30 polymers
Theoretical massNumber of molelcules
Total (without water)707,55430
Polymers707,55430
Non-polymers00
Water0
TypeNameSymmetry operationNumber
point symmetry operation5
4
A: Capsid protein VP1
B: Capsid protein VP3
C: Capsid protein VP2
D: Capsid protein VP4
E: 2H12 Fab heavy chain
F: 2H12 Fab light chain
x 6


  • icosahedral 23 hexamer
  • 849 kDa, 36 polymers
Theoretical massNumber of molelcules
Total (without water)849,06536
Polymers849,06536
Non-polymers00
Water0
TypeNameSymmetry operationNumber
point symmetry operation6
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 ... , 4 types, 4 molecules ABCD

#1: Protein Capsid protein VP1 /


Mass: 32920.309 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Human enterovirus D68 / References: UniProt: A0A097BW12
#2: Protein Capsid protein VP3 /


Mass: 27112.814 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Human enterovirus D68 / References: UniProt: A0A097BW12
#3: Protein Capsid protein VP2 /


Mass: 27567.135 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Human enterovirus D68 / References: UniProt: A0A097BW12
#4: Protein Capsid protein VP4 /


Mass: 7336.960 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Human enterovirus D68 / References: UniProt: A0A097BW12

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Antibody , 2 types, 2 molecules EF

#5: Antibody 2H12 Fab heavy chain


Mass: 22990.736 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Mus musculus (house mouse)
#6: Antibody 2H12 Fab light chain


Mass: 23582.920 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Mus musculus (house 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
1Enterovirus D68 in complex with 2H12 FabEnterovirus 68COMPLEXall0MULTIPLE SOURCES
2Enterovirus D68Enterovirus 68VIRUS#1-#41NATURAL
32H12 FabORGANELLE OR CELLULAR COMPONENT#5-#61NATURAL
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
12Enterovirus D6842789
23Mus musculus (house mouse)10090
Details of virusEmpty: NO / Enveloped: YES / Isolate: STRAIN / Type: VIRION
Buffer solutionpH: 7
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 FIELDBright-field microscopy
Image recordingElectron dose: 38 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.10.1_2155: / Classification: refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.6 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 1816 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0027776
ELECTRON MICROSCOPYf_angle_d0.54710579
ELECTRON MICROSCOPYf_dihedral_angle_d7.4816986
ELECTRON MICROSCOPYf_chiral_restr0.0411180
ELECTRON MICROSCOPYf_plane_restr0.0051355

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