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- EMDB-7902: REGN3471 antibody Fab in complex with Ebola virus GP -

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Entry
Database: EMDB / ID: EMD-7902
TitleREGN3471 antibody Fab in complex with Ebola virus GP
Map dataREGN3471 antibody Fab in complex with Ebola virus GP
Sample
  • Complex: REGN3471 antibody Fab in complex with Ebola virus GP
Biological speciesEbola virus - Mayinga, Zaire, 1976
Methodsingle particle reconstruction / negative staining / Resolution: 21.0 Å
AuthorsTurner H / Murin CD / Ward AB
CitationJournal: J Infect Dis / Year: 2018
Title: Development of Clinical-Stage Human Monoclonal Antibodies That Treat Advanced Ebola Virus Disease in Nonhuman Primates.
Authors: Kristen E Pascal / Drew Dudgeon / John C Trefry / Manu Anantpadma / Yasuteru Sakurai / Charles D Murin / Hannah L Turner / Jeanette Fairhurst / Marcela Torres / Ashique Rafique / Ying Yan / ...Authors: Kristen E Pascal / Drew Dudgeon / John C Trefry / Manu Anantpadma / Yasuteru Sakurai / Charles D Murin / Hannah L Turner / Jeanette Fairhurst / Marcela Torres / Ashique Rafique / Ying Yan / Ashok Badithe / Kevin Yu / Terra Potocky / Sandra L Bixler / Taylor B Chance / William D Pratt / Franco D Rossi / Joshua D Shamblin / Suzanne E Wollen / Justine M Zelko / Ricardo Carrion / Gabriella Worwa / Hilary M Staples / Darya Burakov / Robert Babb / Gang Chen / Joel Martin / Tammy T Huang / Karl Erlandson / Melissa S Willis / Kimberly Armstrong / Thomas M Dreier / Andrew B Ward / Robert A Davey / Margaret L M Pitt / Leah Lipsich / Peter Mason / William Olson / Neil Stahl / Christos A Kyratsous /
Abstract: BACKGROUND: For most classes of drugs, rapid development of therapeutics to treat emerging infections is challenged by the timelines needed to identify compounds with the desired efficacy, safety, ...BACKGROUND: For most classes of drugs, rapid development of therapeutics to treat emerging infections is challenged by the timelines needed to identify compounds with the desired efficacy, safety, and pharmacokinetic profiles. Fully human monoclonal antibodies (mAbs) provide an attractive method to overcome many of these hurdles to rapidly produce therapeutics for emerging diseases.
METHODS: In this study, we deployed a platform to generate, test, and develop fully human antibodies to Zaire ebolavirus. We obtained specific anti-Ebola virus (EBOV) antibodies by immunizing ...METHODS: In this study, we deployed a platform to generate, test, and develop fully human antibodies to Zaire ebolavirus. We obtained specific anti-Ebola virus (EBOV) antibodies by immunizing VelocImmune mice that use human immunoglobulin variable regions in their humoral responses.
RESULTS: Of the antibody clones isolated, 3 were selected as best at neutralizing EBOV and triggering FcγRIIIa. Binding studies and negative-stain electron microscopy revealed that the 3 selected ...RESULTS: Of the antibody clones isolated, 3 were selected as best at neutralizing EBOV and triggering FcγRIIIa. Binding studies and negative-stain electron microscopy revealed that the 3 selected antibodies bind to non-overlapping epitopes, including a potentially new protective epitope not targeted by other antibody-based treatments. When combined, a single dose of a cocktail of the 3 antibodies protected nonhuman primates (NHPs) from EBOV disease even after disease symptoms were apparent.
CONCLUSIONS: This antibody cocktail provides complementary mechanisms of actions, incorporates novel specificities, and demonstrates high-level postexposure protection from lethal EBOV disease in ...CONCLUSIONS: This antibody cocktail provides complementary mechanisms of actions, incorporates novel specificities, and demonstrates high-level postexposure protection from lethal EBOV disease in NHPs. It is now undergoing testing in normal healthy volunteers in preparation for potential use in future Ebola epidemics.
History
DepositionMay 23, 2018-
Header (metadata) releaseJun 13, 2018-
Map releaseJun 13, 2018-
UpdateDec 12, 2018-
Current statusDec 12, 2018Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 3.5
  • Imaged by UCSF Chimera
  • Download
  • Surface view colored by cylindrical radius
  • Surface level: 3.5
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_7902.png

Downloads & links

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Map

FileDownload / File: emd_7902.map.gz / Format: CCP4 / Size: 2 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationREGN3471 antibody Fab in complex with Ebola virus GP
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
4.1 Å/pix.
x 80 pix.
= 328. Å		4.1 Å/pix.
x 80 pix.
= 328. Å		4.1 Å/pix.
x 80 pix.
= 328. Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 4.1 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 3.5 / Movie #1: 3.5
Minimum - Maximum-15.897512000000001 - 14.543581
Average (Standard dev.)-0.0010277 (±0.9724852)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions808080
Spacing808080
CellA=B=C: 328.0 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z4.14.14.1
M x/y/z808080
origin x/y/z0.0000.0000.000
length x/y/z328.000328.000328.000
α/β/γ90.00090.00090.000
start NX/NY/NZ-153-266-98
NX/NY/NZ528514389
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS808080
D min/max/mean-15.89814.544-0.001

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Supplemental data

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Sample components

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Entire : REGN3471 antibody Fab in complex with Ebola virus GP

EntireName: REGN3471 antibody Fab in complex with Ebola virus GP
Components
  • Complex: REGN3471 antibody Fab in complex with Ebola virus GP

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Supramolecule #1: REGN3471 antibody Fab in complex with Ebola virus GP

SupramoleculeName: REGN3471 antibody Fab in complex with Ebola virus GP / type: complex / ID: 1 / Parent: 0
Details: Fab fragment generated by proteolytic cleavage of IgG antibody with papain.
Source (natural)Organism: Ebola virus - Mayinga, Zaire, 1976
Recombinant expressionOrganism: Drosophila melanogaster (fruit fly) / Recombinant cell: S2 / Recombinant plasmid: pMT-puro

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Experimental details

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Structure determination

Methodnegative staining
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration0.02 mg/mL
BufferpH: 7.4
Component:
ConcentrationFormulaName
150.0 mMNaClsodium chloride
20.0 mMC4H11NO3Tris

Details: Solution was made from 10x concentration stock.
StainingType: NEGATIVE / Material: uranyl formate
Details: Stained using 2% uranyl formate on carbon-coated grids.
GridModel: Homemade / Material: COPPER / Mesh: 400 / Support film - Material: CARBON / Support film - topology: CONTINUOUS / Pretreatment - Type: PLASMA CLEANING / Pretreatment - Atmosphere: OTHER
DetailsThis sample was monodisperse.

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Electron microscopy

MicroscopeFEI TECNAI SPIRIT
Image recordingFilm or detector model: TVIPS TEMCAM-F416 (4k x 4k) / Digitization - Dimensions - Width: 4096 pixel / Digitization - Dimensions - Height: 4096 pixel / Number grids imaged: 1 / Number real images: 70 / Average exposure time: 0.6 sec. / Average electron dose: 30.0 e/Å2
Electron beamAcceleration voltage: 120 kV / Electron source: LAB6
Electron opticsC2 aperture diameter: 100.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.2 mm / Nominal defocus min: 1.0 µm / Nominal magnification: 52000
Sample stageSpecimen holder model: SIDE ENTRY, EUCENTRIC
Experimental equipment
Model: Tecnai Spirit / Image courtesy: FEI Company

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Image processing

Startup modelType of model: OTHER / Details: Common lines model
Final reconstructionApplied symmetry - Point group: C3 (3 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 21.0 Å / Resolution method: FSC 0.5 CUT-OFF / Software - Name: EMAN2 (ver. 2.1) / Number images used: 20266
Initial angle assignmentType: COMMON LINE / Software - Name: EMAN2
Final angle assignmentType: ANGULAR RECONSTITUTION / Software - Name: EMAN2

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