Journal: Cell / Year: 2017 Title: Antibodies from a Human Survivor Define Sites of Vulnerability for Broad Protection against Ebolaviruses. Authors: Anna Z Wec / Andrew S Herbert / Charles D Murin / Elisabeth K Nyakatura / Dafna M Abelson / J Maximilian Fels / Shihua He / Rebekah M James / Marc-Antoine de La Vega / Wenjun Zhu / Russell R ...Authors: Anna Z Wec / Andrew S Herbert / Charles D Murin / Elisabeth K Nyakatura / Dafna M Abelson / J Maximilian Fels / Shihua He / Rebekah M James / Marc-Antoine de La Vega / Wenjun Zhu / Russell R Bakken / Eileen Goodwin / Hannah L Turner / Rohit K Jangra / Larry Zeitlin / Xiangguo Qiu / Jonathan R Lai / Laura M Walker / Andrew B Ward / John M Dye / Kartik Chandran / Zachary A Bornholdt / Abstract: Experimental monoclonal antibody (mAb) therapies have shown promise for treatment of lethal Ebola virus (EBOV) infections, but their species-specific recognition of the viral glycoprotein (GP) has ...Experimental monoclonal antibody (mAb) therapies have shown promise for treatment of lethal Ebola virus (EBOV) infections, but their species-specific recognition of the viral glycoprotein (GP) has limited their use against other divergent ebolaviruses associated with human disease. Here, we mined the human immune response to natural EBOV infection and identified mAbs with exceptionally potent pan-ebolavirus neutralizing activity and protective efficacy against three virulent ebolaviruses. These mAbs recognize an inter-protomer epitope in the GP fusion loop, a critical and conserved element of the viral membrane fusion machinery, and neutralize viral entry by targeting a proteolytically primed, fusion-competent GP intermediate (GP) generated in host cell endosomes. Only a few somatic hypermutations are required for broad antiviral activity, and germline-approximating variants display enhanced GP recognition, suggesting that such antibodies could be elicited more efficiently with suitably optimized GP immunogens. Our findings inform the development of both broadly effective immunotherapeutics and vaccines against filoviruses.
History
Deposition
Apr 21, 2017
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Header (metadata) release
Jun 7, 2017
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Map release
Jun 7, 2017
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Update
Feb 14, 2018
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Current status
Feb 14, 2018
Processing site: RCSB / Status: Released
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Structure visualization
Movie
Surface view with section colored by density value
Name: EBOVGPdMuc:ADI-16061 / type: complex / ID: 1 / Parent: 0 Details: Complex of recombinant Ebola virus glycoprotein and recombinant human IgG1 Fab from survivor of infection.
Name: ADI-16061 Fab / type: complex / ID: 3 / Parent: 1 Details: Fab fragment generated by proteolytic cleavage of IgG antibody, expressed in plant system.
Source (natural)
Organism: Homo sapiens (human)
Recombinant expression
Organism: Nicotiana benthamiana (plant)
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Experimental details
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Structure determination
Method
negative staining
Processing
single particle reconstruction
Aggregation state
particle
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Sample preparation
Concentration
0.03 mg/mL
Buffer
pH: 7.4 Component:
Concentration
Formula
Name
150.0 mM
NaCl
sodium chloride
20.0 mM
Tris
Tris
Details: Solutions were made from a 10X stock and filtered sterilized.
Staining
Type: NEGATIVE / Material: Uranyl Formate Details: Negatively stained EM specimens were prepared using a side-blotting technique and uranyl-formate stain.
Grid
Model: Protochip / Material: COPPER / Mesh: 400 / Support film - Material: CARBON / Support film - topology: CONTINUOUS / Pretreatment - Type: PLASMA CLEANING / Pretreatment - Atmosphere: OTHER
Details
Monodisperse sample deposited on negative stain grid.
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Electron microscopy
Microscope
FEI TECNAI SPIRIT
Image recording
Film or detector model: TVIPS TEMCAM-F416 (4k x 4k) / Number grids imaged: 1 / Number real images: 53 / Average electron dose: 2.0 e/Å2
Electron beam
Acceleration voltage: 120 kV / Electron source: LAB6
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