Convergence of a common solution for broad ebolavirus neutralization by glycan cap-directed human antibodies

Cell Rep. 2021 Apr 13;35(2):108984. doi: 10.1016/j.celrep.2021.108984.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Antibodies, Monoclonal / chemistry
  • Antibodies, Monoclonal / metabolism
  • Antibodies, Monoclonal / pharmacology*
  • Antibodies, Neutralizing / chemistry
  • Antibodies, Neutralizing / metabolism
  • Antibodies, Neutralizing / pharmacology*
  • Antibodies, Viral / chemistry
  • Antibodies, Viral / metabolism
  • Antibodies, Viral / pharmacology*
  • Antibody Specificity
  • Binding Sites
  • Cryoelectron Microscopy
  • Ebolavirus / drug effects*
  • Ebolavirus / growth & development
  • Ebolavirus / immunology
  • Ebolavirus / pathogenicity
  • Epitopes / chemistry
  • Epitopes / immunology
  • Female
  • HEK293 Cells
  • HeLa Cells
  • Hemorrhagic Fever, Ebola / drug therapy*
  • Hemorrhagic Fever, Ebola / immunology
  • Hemorrhagic Fever, Ebola / pathology
  • Hemorrhagic Fever, Ebola / virology
  • Humans
  • Jurkat Cells
  • Mice
  • Models, Molecular
  • Polysaccharides / chemistry
  • Polysaccharides / immunology
  • Protein Binding
  • Protein Conformation, beta-Strand
  • Protein Interaction Domains and Motifs
  • Sequence Alignment
  • Sequence Homology, Amino Acid
  • Viral Envelope Proteins / antagonists & inhibitors
  • Viral Envelope Proteins / chemistry*
  • Viral Envelope Proteins / genetics
  • Viral Envelope Proteins / metabolism

Substances

  • Antibodies, Monoclonal
  • Antibodies, Neutralizing
  • Antibodies, Viral
  • Epitopes
  • Polysaccharides
  • Viral Envelope Proteins