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- PDB-7m8l: EBOV GP bound to rEBOV-442 and rEBOV-515 Fabs -

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Basic information

Entry
Database: PDB / ID: 7m8l
TitleEBOV GP bound to rEBOV-442 and rEBOV-515 Fabs
Components
  • (Virion spike glycoprotein ...) x 2
  • (rEBOV-442 Fab ...) x 2
  • (rEBOV-515 Fab ...) x 2
KeywordsVIRAL PROTEIN/IMMUNE SYSTEM / ebolavirus / EBOV / antibody / antibody therapeutic / mAbs / filovirus / VIRAL PROTEIN / VIRAL PROTEIN-IMMUNE SYSTEM complex
Function / homologyFiloviruses glycoprotein, extracellular domain / Filoviruses glycoprotein / Filovirus glycoprotein / extracellular region / membrane / Virion spike glycoprotein / Virion spike glycoprotein
Function and homology information
Biological speciesEbola virus
Homo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.9 Å
AuthorsMurin, C.D. / Ward, A.B.
Funding support United States, 2items
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, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 10, 2021Provider: repository / Type: Initial release

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Structure visualization

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Assembly

Deposited unit
A: Virion spike glycoprotein 1
G: rEBOV-442 Fab heavy chain
J: rEBOV-442 Fab light chain
D: Virion spike glycoprotein 2
M: rEBOV-515 Fab heavy chain
P: rEBOV-515 Fab light chain
B: Virion spike glycoprotein 1
H: rEBOV-442 Fab heavy chain
K: rEBOV-442 Fab light chain
E: Virion spike glycoprotein 2
N: rEBOV-515 Fab heavy chain
Q: rEBOV-515 Fab light chain
C: Virion spike glycoprotein 1
I: rEBOV-442 Fab heavy chain
L: rEBOV-442 Fab light chain
F: Virion spike glycoprotein 2
O: rEBOV-515 Fab heavy chain
R: rEBOV-515 Fab light chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)468,88833
Polymers460,82318
Non-polymers8,06515
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Virion spike glycoprotein ... , 2 types, 6 molecules ABCDEF

#1: Protein Virion spike glycoprotein 1


Mass: 34978.613 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Ebola virus / Gene: GP / Production host: Homo sapiens (human) / References: UniProt: A0A1C4HDV6
#4: Protein Virion spike glycoprotein 2


Mass: 22158.592 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Ebola virus / Gene: GP / Production host: Homo sapiens (human) / References: UniProt: A0A0E3XK95

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Antibody , 4 types, 12 molecules GHIJKLMNOPQR

#2: Antibody rEBOV-442 Fab heavy chain


Mass: 25179.199 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)
#3: Antibody rEBOV-442 Fab light chain


Mass: 23715.314 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)
#5: Antibody rEBOV-515 Fab heavy chain


Mass: 24047.846 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)
#6: Antibody rEBOV-515 Fab light chain


Mass: 23528.092 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)

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Sugars , 3 types, 15 molecules

#7: Polysaccharide
alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2- ...alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 910.823 Da / Num. of mol.: 6
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpa1-3[DManpa1-6]DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/3,5,4/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5][a1122h-1a_1-5]/1-1-2-3-3/a4-b1_b4-c1_c3-d1_c6-e1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{[(3+1)][a-D-Manp]{}[(6+1)][a-D-Manp]{}}}}LINUCSPDB-CARE
#8: Polysaccharide 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 424.401 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/1,2,1/[a2122h-1b_1-5_2*NCC/3=O]/1-1/a4-b1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}LINUCSPDB-CARE
#9: Sugar
ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0

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Details

Has ligand of interestN

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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: Complex of mucin deleted Ebola virus GP (Makona variant) bound to rEBOV-442 and rEBOV-515 Fabs
Type: COMPLEX / Entity ID: #1-#6 / Source: RECOMBINANT
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
11Ebola virus1570291
21Homo sapiens (human)9606
Source (recombinant)Organism: Homo sapiens (human)
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: 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
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C3 (3 fold cyclic)
3D reconstructionResolution: 3.9 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 21285 / Symmetry type: POINT

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