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- EMDB-31060: EV-D68 in complex with 2H12 Fab (State 3) -

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Basic information

Entry
Database: EMDB / ID: EMD-31060
TitleEV-D68 in complex with 2H12 Fab (State 3)Enterovirus 68
Map data2H12 A2
Sample
  • Complex: Enterovirus D68 in complex with 2H12 FabEnterovirus 68
    • Complex: Enterovirus D68Enterovirus 68
      • Protein or peptide: Capsid protein VP1
      • Protein or peptide: Capsid protein VP3
      • Protein or peptide: Capsid protein VP2
    • Complex: 2H12 Fab
      • Protein or peptide: Fab 2H12 heavy chain
      • Protein or peptide: Fab 2H12 light chain
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 / endocytosis involved in viral entry into host cell / cytoplasmic vesicle membrane / : ...: / 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 / endocytosis involved in viral entry into host cell / cytoplasmic vesicle membrane / : / 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 / structural molecule activity / virion attachment to host cell / 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 / DNA/RNA polymerase superfamily / Peptidase S1, PA clan / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
Biological speciesEnterovirus D68 / Mus musculus (house mouse) / EV68, EV-68 / mouse (mice)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.6 Å
AuthorsXu C / Cong Y
Funding support China, 1 items
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 13, 2021-
Header (metadata) releaseMar 31, 2021-
Map releaseMar 31, 2021-
UpdateJun 2, 2021-
Current statusJun 2, 2021Processing site: PDBj / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.014
  • Imaged by UCSF Chimera
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  • Surface view colored by radius
  • Surface level: 0.014
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7ecy
  • Surface level: 0.014
  • Imaged by UCSF Chimera
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  • Simplified surface model + fitted atomic model
  • Atomic modelsPDB-7ecy
  • Imaged by Jmol
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_31060.png

Downloads & links

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Map

FileDownload / File: emd_31060.map.gz / Format: CCP4 / Size: 307.5 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotation2H12 A2
Voxel sizeX=Y=Z: 1.318 Å
Density
Contour LevelBy AUTHOR: 0.014 / Movie #1: 0.014
Minimum - Maximum-0.049911242 - 0.0936147
Average (Standard dev.)-1.5866446e-05 (±0.0050055077)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions432432432
Spacing432432432
CellA=B=C: 569.376 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.3181.3181.318
M x/y/z432432432
origin x/y/z0.0000.0000.000
length x/y/z569.376569.376569.376
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ400400400
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS432432432
D min/max/mean-0.0500.094-0.000

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Supplemental data

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Sample components

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Entire : Enterovirus D68 in complex with 2H12 Fab

EntireName: Enterovirus D68 in complex with 2H12 FabEnterovirus 68
Components
  • Complex: Enterovirus D68 in complex with 2H12 FabEnterovirus 68
    • Complex: Enterovirus D68Enterovirus 68
      • Protein or peptide: Capsid protein VP1
      • Protein or peptide: Capsid protein VP3
      • Protein or peptide: Capsid protein VP2
    • Complex: 2H12 Fab
      • Protein or peptide: Fab 2H12 heavy chain
      • Protein or peptide: Fab 2H12 light chain

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Supramolecule #1: Enterovirus D68 in complex with 2H12 Fab

SupramoleculeName: Enterovirus D68 in complex with 2H12 Fab / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all

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Supramolecule #2: Enterovirus D68

SupramoleculeName: Enterovirus D68 / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1-#3
Source (natural)Organism: Enterovirus D68

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Supramolecule #3: 2H12 Fab

SupramoleculeName: 2H12 Fab / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #4-#5
Source (natural)Organism: Mus musculus (house mouse)

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Macromolecule #1: Capsid protein VP1

MacromoleculeName: Capsid protein VP1 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: EV68, EV-68
Molecular weightTheoretical: 32.920309 KDa
SequenceString: IESIIKTATD TVKSEINAEL GVVPSLNAVE TGATSNTEPE EAIQTRTVIN QHGVSETLVE NFLSRAALVS KRSFEYKDHT SSTARADKN FFKWTINTRS FVQLRRKLEL FTYLRFDAEI TILTTVAVNG SGNNTYVGLP DLTLQAMFVP TGALTPEKQD S FHWQSGSN ...String:
IESIIKTATD TVKSEINAEL GVVPSLNAVE TGATSNTEPE EAIQTRTVIN QHGVSETLVE NFLSRAALVS KRSFEYKDHT SSTARADKN FFKWTINTRS FVQLRRKLEL FTYLRFDAEI TILTTVAVNG SGNNTYVGLP DLTLQAMFVP TGALTPEKQD S FHWQSGSN ASVFFKISDP PARITIPFMC INSAYSVFYD GFAGFEKNGL YGINPADTIG NLCVRIVNEH QPVGFTVTVR VY MKPKHIK AWAPRPPRTL PYMSIANANY KGKERAPNAL SAIIGNRDSV KTMPHNIVNT

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Macromolecule #2: Capsid protein VP3

MacromoleculeName: Capsid protein VP3 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: EV68, EV-68
Molecular weightTheoretical: 27.112814 KDa
SequenceString: GVPTYLLPGS GQFLTTDDHS SAPALPCFNP TPEMHIPGQV RNMLEVVQVE SMMEINNTES AVGMERLKVD ISALTDVDQL LFNIPLDIQ LDGPLRNTLV GNISRYYTHW SGSLEMTFMF CGSFMAAGKL ILCYTPPGGS CPTTRETAML GTHIVWDFGL Q SSVTLIIP ...String:
GVPTYLLPGS GQFLTTDDHS SAPALPCFNP TPEMHIPGQV RNMLEVVQVE SMMEINNTES AVGMERLKVD ISALTDVDQL LFNIPLDIQ LDGPLRNTLV GNISRYYTHW SGSLEMTFMF CGSFMAAGKL ILCYTPPGGS CPTTRETAML GTHIVWDFGL Q SSVTLIIP WISGSHYRMF NNDAKSTNAN VGYVTCFMQT NLIVPSESSD TCSLIGFIAA KDDFSLRLMR DSPDIGQLDH LH AAEAAYQ

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Macromolecule #3: Capsid protein VP2

MacromoleculeName: Capsid protein VP2 / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: EV68, EV-68
Molecular weightTheoretical: 27.567135 KDa
SequenceString: SPSAEACGYS DRVLQLKLGN SAIVTQEAAN YCCAYGEWPN YLPDHEAVAI DKPTQPETAT DRFYTLKSVK WETGSTGWWW KLPDALNNI GMFGQNVQHH YLYRSGFLIH VQCNATKFHQ GALLVVAIPE HQRGAHNTNT SPGFDDIMKG EEGGTFNHPY V LDDGTSLA ...String:
SPSAEACGYS DRVLQLKLGN SAIVTQEAAN YCCAYGEWPN YLPDHEAVAI DKPTQPETAT DRFYTLKSVK WETGSTGWWW KLPDALNNI GMFGQNVQHH YLYRSGFLIH VQCNATKFHQ GALLVVAIPE HQRGAHNTNT SPGFDDIMKG EEGGTFNHPY V LDDGTSLA CATIFPHQWI NLRTNNSATI VLPWMNAAPM DFPLRHNQWT LAIIPVVPLG TRTTSSMVPI TVSIAPMCCE FN GLRHAIT Q

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Macromolecule #4: Fab 2H12 heavy chain

MacromoleculeName: Fab 2H12 heavy chain / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: mouse (mice)
Molecular weightTheoretical: 22.990736 KDa
SequenceString: QVQLQQPGAE LVMPGASVKM SCKASGYTFT DYWMHWVKQR PGQGLEWIGA IDTSDSYTTY NRKFKGKATL TVDESSSTAY MQLISLTSE DSAVYYCARG GGGNSPFAYW GQGTLVTVSA AKTTAPSVYP LAPVCGDTTG SSVTLGCLVK GYFPEPVTLT W NSGSLSSG ...String:
QVQLQQPGAE LVMPGASVKM SCKASGYTFT DYWMHWVKQR PGQGLEWIGA IDTSDSYTTY NRKFKGKATL TVDESSSTAY MQLISLTSE DSAVYYCARG GGGNSPFAYW GQGTLVTVSA AKTTAPSVYP LAPVCGDTTG SSVTLGCLVK GYFPEPVTLT W NSGSLSSG VHTFPAVLQS DLYTLSSSVT VTSSTWPSQS ITCNVAHPAS STKVDKKI

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Macromolecule #5: Fab 2H12 light chain

MacromoleculeName: Fab 2H12 light chain / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: mouse (mice)
Molecular weightTheoretical: 23.58292 KDa
SequenceString: DIQMTQSPSS LSASLGERVS LTCRASQDIG SSLNWLQQEP DGTIKRLIYA TSSLDSGVPK RFSGSRSGSD YSLTISSLES EDFVDYYCL QYASFPLTFG AGTKLELKRA DAAPTVSIFP PSSEQLTSGG ASVVCFLNNF YPKDINVKWK IDGSERQNGV L NSWTDQDS ...String:
DIQMTQSPSS LSASLGERVS LTCRASQDIG SSLNWLQQEP DGTIKRLIYA TSSLDSGVPK RFSGSRSGSD YSLTISSLES EDFVDYYCL QYASFPLTFG AGTKLELKRA DAAPTVSIFP PSSEQLTSGG ASVVCFLNNF YPKDINVKWK IDGSERQNGV L NSWTDQDS KDSTYSMSST LTLTKDEYER HNSYTCEATH KTSTSPIVKS FNRNEC

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 38.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.6 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 2647

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