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- EMDB-23719: EBOV GP bound to rEBOV-442 and rEBOV-515 Fabs -

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Basic information

Entry
Database: EMDB / ID: EMD-23719
TitleEBOV GP bound to rEBOV-442 and rEBOV-515 Fabs
Map dataMucin deleted Ebola virus GP (Makona variant) in complex with rEBOV-442 and rEBOV-515 Fabs.
Sample
  • Complex: Complex of mucin deleted Ebola virus GP (Makona variant) bound to rEBOV-442 and rEBOV-515 Fabs
    • Protein or peptide: Virion spike glycoprotein 1
    • Protein or peptide: rEBOV-442 Fab heavy chain
    • Protein or peptide: rEBOV-442 Fab light chain
    • Protein or peptide: Virion spike glycoprotein 2
    • Protein or peptide: rEBOV-515 Fab heavy chain
    • Protein or peptide: rEBOV-515 Fab light chain
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
Function / homologyFiloviruses glycoprotein, extracellular domain / Filoviruses glycoprotein / Filovirus glycoprotein / Envelope glycoprotein GP2-like, HR1-HR2 / extracellular region / membrane / Virion spike glycoprotein / Virion spike glycoprotein
Function and homology information
Biological speciesEbola virus / Homo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.9 Å
AuthorsMurin CD / Ward AB
Funding support United States, 2 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)U19 AI109762 United States
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)U19 AI142785 United States
CitationJournal: Cell / Year: 2021
Title: Pan-ebolavirus protective therapy by two multifunctional human antibodies.
Authors: Pavlo Gilchuk / Charles D Murin / Robert W Cross / Philipp A Ilinykh / Kai Huang / Natalia Kuzmina / Viktoriya Borisevich / Krystle N Agans / Joan B Geisbert / Seth J Zost / Rachel S Nargi / ...Authors: Pavlo Gilchuk / Charles D Murin / Robert W Cross / Philipp A Ilinykh / Kai Huang / Natalia Kuzmina / Viktoriya Borisevich / Krystle N Agans / Joan B Geisbert / Seth J Zost / Rachel S Nargi / Rachel E Sutton / Naveenchandra Suryadevara / Robin G Bombardi / Robert H Carnahan / Alexander Bukreyev / Thomas W Geisbert / Andrew B Ward / James E Crowe /
Abstract: Ebolaviruses cause a severe and often fatal illness with the potential for global spread. Monoclonal antibody-based treatments that have become available recently have a narrow therapeutic spectrum ...Ebolaviruses cause a severe and often fatal illness with the potential for global spread. Monoclonal antibody-based treatments that have become available recently have a narrow therapeutic spectrum and are ineffective against ebolaviruses other than Ebola virus (EBOV), including medically important Bundibugyo (BDBV) and Sudan (SUDV) viruses. Here, we report the development of a therapeutic cocktail comprising two broadly neutralizing human antibodies, rEBOV-515 and rEBOV-442, that recognize non-overlapping sites on the ebolavirus glycoprotein (GP). Antibodies in the cocktail exhibited synergistic neutralizing activity, resisted viral escape, and possessed differing requirements for their Fc-regions for optimal in vivo activities. The cocktail protected non-human primates from ebolavirus disease caused by EBOV, BDBV, or SUDV with high therapeutic effectiveness. High-resolution structures of the cocktail antibodies in complex with GP revealed the molecular determinants for neutralization breadth and potency. This study provides advanced preclinical data to support clinical development of this cocktail for pan-ebolavirus therapy.
History
DepositionMar 30, 2021-
Header (metadata) releaseNov 10, 2021-
Map releaseNov 10, 2021-
UpdateNov 10, 2021-
Current statusNov 10, 2021Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.0275
  • Imaged by UCSF Chimera
  • Download
  • Surface view colored by cylindrical radius
  • Surface level: 0.0275
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7m8l
  • Surface level: 0.0275
  • Imaged by UCSF Chimera
  • Download
Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_23719.png

Downloads & links

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Map

FileDownload / File: emd_23719.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationMucin deleted Ebola virus GP (Makona variant) in complex with rEBOV-442 and rEBOV-515 Fabs.
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.03 Å/pix.
x 320 pix.
= 329.6 Å		1.03 Å/pix.
x 320 pix.
= 329.6 Å		1.03 Å/pix.
x 320 pix.
= 329.6 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.03 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0275 / Movie #1: 0.0275
Minimum - Maximum-0.11153408 - 0.17126594
Average (Standard dev.)0.000197357 (±0.0031811397)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 329.59998 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.031.031.03
M x/y/z320320320
origin x/y/z0.0000.0000.000
length x/y/z329.600329.600329.600
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS320320320
D min/max/mean-0.1120.1710.000

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Supplemental data

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Sample components

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Entire : Complex of mucin deleted Ebola virus GP (Makona variant) bound to...

EntireName: Complex of mucin deleted Ebola virus GP (Makona variant) bound to rEBOV-442 and rEBOV-515 Fabs
Components
  • Complex: Complex of mucin deleted Ebola virus GP (Makona variant) bound to rEBOV-442 and rEBOV-515 Fabs
    • Protein or peptide: Virion spike glycoprotein 1
    • Protein or peptide: rEBOV-442 Fab heavy chain
    • Protein or peptide: rEBOV-442 Fab light chain
    • Protein or peptide: Virion spike glycoprotein 2
    • Protein or peptide: rEBOV-515 Fab heavy chain
    • Protein or peptide: rEBOV-515 Fab light chain
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: Complex of mucin deleted Ebola virus GP (Makona variant) bound to...

SupramoleculeName: Complex of mucin deleted Ebola virus GP (Makona variant) bound to rEBOV-442 and rEBOV-515 Fabs
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#6
Source (natural)Organism: Ebola virus
Recombinant expressionOrganism: Homo sapiens (human)

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Macromolecule #1: Virion spike glycoprotein 1

MacromoleculeName: Virion spike glycoprotein 1 / type: protein_or_peptide / ID: 1 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Ebola virus
Molecular weightTheoretical: 34.978613 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MDAMKRGLCC VLLLCGAVFV SPSQEIHARF RRGARSIPLG VIHNSTLQVS DVDKLVCRDK LSSTNQLRSV GLNLEGNGVA TDVPSVTKR WGFRSGVPPK VVNYEAGEWA ENCYNLEIKK PDGSECLPAA PDGIRGFPRC RYVHKVSGTG PCAGDFAFHK E GAFFLYDR ...String:
MDAMKRGLCC VLLLCGAVFV SPSQEIHARF RRGARSIPLG VIHNSTLQVS DVDKLVCRDK LSSTNQLRSV GLNLEGNGVA TDVPSVTKR WGFRSGVPPK VVNYEAGEWA ENCYNLEIKK PDGSECLPAA PDGIRGFPRC RYVHKVSGTG PCAGDFAFHK E GAFFLYDR LASTVIYRGT TFAEGVVAFL ILPQAKKDFF SSHPLREPVN ATEDPSSGYY STTIRYQATG FGTNETEYLF EV DNLTYVQ LESRFTPQFL LQLNETIYAS GKRSNTTGKL IWKVNPEIDT TIGEWAFWET KKNLTRKIRS EELSFT

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Macromolecule #2: rEBOV-442 Fab heavy chain

MacromoleculeName: rEBOV-442 Fab heavy chain / type: protein_or_peptide / ID: 2 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 25.179199 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: EVQLVESGGG LVKPGGSLRL SCTGSGGTGF TFKYAGMSWV RQAPGKGPEW IGRIKSRIDG GTTDYAAPVK DRFIVSRDDS RNTLYLQMN SLKTEDTAVY YCATGSGKGP SASFGESYYY YDFINVWGKG TTVTVSSAST KGPSVFPLAP SSKSTSGGTA A LGCLVKDY ...String:
EVQLVESGGG LVKPGGSLRL SCTGSGGTGF TFKYAGMSWV RQAPGKGPEW IGRIKSRIDG GTTDYAAPVK DRFIVSRDDS RNTLYLQMN SLKTEDTAVY YCATGSGKGP SASFGESYYY YDFINVWGKG TTVTVSSAST KGPSVFPLAP SSKSTSGGTA A LGCLVKDY FPEPVTVSWN SGALTSGVHT FPAVLQSSGL YSLSSVVTVP SSSLGTQTYI CNVNHKPSNT KVDKKVEPKS C

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Macromolecule #3: rEBOV-442 Fab light chain

MacromoleculeName: rEBOV-442 Fab light chain / type: protein_or_peptide / ID: 3 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 23.715314 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: ESVLTQSPGT LSLSPGERAT LSCRASQSIS RKYLAWYQQK PGQAPRLLIY GSSSRATGIP DRFSGSGSGT DFTLTISRLE PEDFAVYYC HQYESSPWTF GQGTKVEIKR TVAAPSVFIF PPSDEQLKSG TASVVCLLNN FYPREAKVQW KVDNALQSGN S QESVTEQD ...String:
ESVLTQSPGT LSLSPGERAT LSCRASQSIS RKYLAWYQQK PGQAPRLLIY GSSSRATGIP DRFSGSGSGT DFTLTISRLE PEDFAVYYC HQYESSPWTF GQGTKVEIKR TVAAPSVFIF PPSDEQLKSG TASVVCLLNN FYPREAKVQW KVDNALQSGN S QESVTEQD SKDSTYSLSS TLTLSKADYE KHKVYACEVT HQGLRSPVTK SFNRGEC

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Macromolecule #4: Virion spike glycoprotein 2

MacromoleculeName: Virion spike glycoprotein 2 / type: protein_or_peptide / ID: 4 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Ebola virus
Molecular weightTheoretical: 22.158592 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: NNNTHHQDTG EESASSGKLG LITNTIAGVA GLITGGRRTR REVIVNAQPK CNPNLHYWTT QDEGAAIGLA WIPYFGPAAE GIYTEGLMH NQDGLICGLR QLANETTQAL QLFLRATTEL RTFSILNRKA IDFLLQRWGG TCHILGPDCC IEPHDWTKNI T DKIDQIIH ...String:
NNNTHHQDTG EESASSGKLG LITNTIAGVA GLITGGRRTR REVIVNAQPK CNPNLHYWTT QDEGAAIGLA WIPYFGPAAE GIYTEGLMH NQDGLICGLR QLANETTQAL QLFLRATTEL RTFSILNRKA IDFLLQRWGG TCHILGPDCC IEPHDWTKNI T DKIDQIIH DDDDKAGWSH PQFEKGGGSG GGSGGGSWSH PQFEK

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Macromolecule #5: rEBOV-515 Fab heavy chain

MacromoleculeName: rEBOV-515 Fab heavy chain / type: protein_or_peptide / ID: 5 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 24.047846 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: QVQLHESGPG LVKPSQTLSL TCTVSGGSIN SAGYYWTWIR QHPGKGLEWI GYIDYTGRTY YNPSLESRVI ISIDTSKNHF SLRLTSVSA ADTAVYYCAR ESSWVSELGR DNWGQGTLVT VSSASTKGPS VFPLAPSSKS TSGGTAALGC LVKDYFPEPV T VSWNSGAL ...String:
QVQLHESGPG LVKPSQTLSL TCTVSGGSIN SAGYYWTWIR QHPGKGLEWI GYIDYTGRTY YNPSLESRVI ISIDTSKNHF SLRLTSVSA ADTAVYYCAR ESSWVSELGR DNWGQGTLVT VSSASTKGPS VFPLAPSSKS TSGGTAALGC LVKDYFPEPV T VSWNSGAL TSGVHTFPAV LQSSGLYSLS SVVTVPSSSL GTQTYICNVN HKPSNTKVDK KVEPKSC

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Macromolecule #6: rEBOV-515 Fab light chain

MacromoleculeName: rEBOV-515 Fab light chain / type: protein_or_peptide / ID: 6 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 23.528092 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: EIVMTQSPAT LPVSPGEGAT LSCRASQSVF TNLAWYQQKP GQAPRLLIYD ASTRATGIPA RFSGSGSGTE FTLTISSLQS EDFAVYYCQ QYNNWPRTYG QGTRVEVKRT VAAPSVFIFP PSDEQLKSGT ASVVCLLNNF YPREAKVQWK VDNALQSGNS Q ESVTEQDS ...String:
EIVMTQSPAT LPVSPGEGAT LSCRASQSVF TNLAWYQQKP GQAPRLLIYD ASTRATGIPA RFSGSGSGTE FTLTISSLQS EDFAVYYCQ QYNNWPRTYG QGTRVEVKRT VAAPSVFIFP PSDEQLKSGT ASVVCLLNNF YPREAKVQWK VDNALQSGNS Q ESVTEQDS KDSTYSLSST LTLSKADYEK HKVYACEVTH QGLRSPVTKS FNRGEC

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Macromolecule #9: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 9 / Number of copies: 6 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

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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: 7.4
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Final reconstructionApplied symmetry - Point group: C3 (3 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 3.9 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 21285
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION
FSC plot (resolution estimation)

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