Structural Basis of Broad Ebolavirus Neutralization by a Human Survivor Antibody

Brandyn R. West, Anna Z. Wec, Crystal L. Moyer, Marnie L. Fusco, Phillipp A. Ilinykh, Kai Huang, Rebekah M. James, Andrew S. Herbert, Sean Hui, Ariel S. Wirchnianski, Eileen Goodwin, M. Javad Aman, Laura M. Walker, John M. Dye, Alexander Bukreyev, Kartik Chandran, Erica Ollmann Saphire

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
JournalUnknown Journal
DOIs
StatePublished - Aug 19 2018

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • Immunology and Microbiology(all)
  • Neuroscience(all)
  • Pharmacology, Toxicology and Pharmaceutics(all)

Fingerprint Dive into the research topics of 'Structural Basis of Broad Ebolavirus Neutralization by a Human Survivor Antibody'. Together they form a unique fingerprint.

Cite this