Abstract
Antibodies that target the glycan cap epitope on the ebolavirus glycoprotein (GP) are common in the adaptive response of survivors. A subset is known to be broadly neutralizing, but the details of their epitopes and basis for neutralization are not well understood. Here, we present cryoelectron microscopy (cryo-EM) structures of diverse glycan cap antibodies that variably synergize with GP base-binding antibodies. These structures describe a conserved site of vulnerability that anchors the mucin-like domains (MLDs) to the glycan cap, which we call the MLD anchor and cradle. Antibodies that bind to the MLD cradle share common features, including use of IGHV1-69 and IGHJ6 germline genes, which exploit hydrophobic residues and form β-hairpin structures to mimic the MLD anchor, disrupt MLD attachment, destabilize GP quaternary structure, and block cleavage events required for receptor binding. Our results provide a molecular basis for ebolavirus neutralization by broadly reactive glycan cap antibodies.
Keywords:
Ebola virus; antibody; antibody therapeutics; broadly neutralizing; ebolaviruses; filoviruses; glycan cap; mAb.
Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Amino Acid Sequence
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Animals
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Antibodies, Monoclonal / chemistry
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Antibodies, Monoclonal / metabolism
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Antibodies, Monoclonal / pharmacology*
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Antibodies, Neutralizing / chemistry
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Antibodies, Neutralizing / metabolism
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Antibodies, Neutralizing / pharmacology*
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Antibodies, Viral / chemistry
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Antibodies, Viral / metabolism
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Antibodies, Viral / pharmacology*
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Antibody Specificity
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Binding Sites
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Cryoelectron Microscopy
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Ebolavirus / drug effects*
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Ebolavirus / growth & development
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Ebolavirus / immunology
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Ebolavirus / pathogenicity
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Epitopes / chemistry
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Epitopes / immunology
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Female
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HEK293 Cells
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HeLa Cells
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Hemorrhagic Fever, Ebola / drug therapy*
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Hemorrhagic Fever, Ebola / immunology
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Hemorrhagic Fever, Ebola / pathology
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Hemorrhagic Fever, Ebola / virology
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Humans
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Jurkat Cells
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Mice
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Models, Molecular
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Polysaccharides / chemistry
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Polysaccharides / immunology
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Protein Binding
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Protein Conformation, beta-Strand
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Protein Interaction Domains and Motifs
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Sequence Alignment
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Sequence Homology, Amino Acid
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Viral Envelope Proteins / antagonists & inhibitors
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Viral Envelope Proteins / chemistry*
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Viral Envelope Proteins / genetics
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Viral Envelope Proteins / metabolism
Substances
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Antibodies, Monoclonal
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Antibodies, Neutralizing
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Antibodies, Viral
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Epitopes
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Polysaccharides
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Viral Envelope Proteins