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Structural Basis of Broad Ebolavirus Neutralization by a Human Survivor Antibody

Nature structural & molecular biology(2019)

引用 27|浏览110
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摘要
The structural features that govern broad-spectrum activity of broadly neutralizing, anti-ebolavirus antibodies (Abs) are currently unknown. Here we describe the first structure of a broadly neutralizing human Ab, ADI-15946, in complex with cleaved Ebola virus glycoprotein (EBOV GPCL). We find that ADI-15946 employs structural mimicry of a conserved interaction between the GP core and the glycan cap β17-β18 loop to inhibit infection. Both endosomal proteolysis of EBOV GP and binding of monoclonal Ab (mAb) FVM09 displace this loop, increase exposure of ADI-15946’s conserved epitope and potentiate neutralization. Our work also illuminated the determinants of ADI-15946’s reduced activity against Sudan virus (SUDV), and enabled rational, structure-guided engineering to enhance binding and neutralization against SUDV while retaining the parental breadth of activity. One Sentence Summary The first crystal structure of a broadly active antibody against surface glycoproteins of ebolaviruses identifies a highly conserved epitope beneath the glycan cap and highlights the molecular requirements for broad ebolavirus neutralization.
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关键词
Diseases,Immunology,Structural biology,Virology,X-ray crystallography,Life Sciences,general,Biochemistry,Protein Structure,Membrane Biology,Biological Microscopy
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