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

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

Authors :
Philipp A. Ilinykh
James E. Crowe
Xiaoli Shen
Alexander Bukreyev
Andrew I. Flyak
Pavlo Gilchuk
Charles D. Murin
Jessica F. Bruhn
Lauren E. Williamson
Aubrey L. Bryan
Jeffrey Copps
Andrew B. Ward
Tanwee Alkutkar
Natalia Kuzmina
Benjamin J. Doranz
Edgar Davidson
Kai Huang
Source :
Cell Reports, Vol 35, Iss 2, Pp 108984-(2021), Cell reports
Publication Year :
2021
Publisher :
Elsevier, 2021.

Abstract

SUMMARY 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.<br />In brief A rare subset of ebolavirus antibodies targeting the glycan cap are broadly neutralizing. Murin et al. report cryo-EM structures and custom in vitro assays identifying a conserved site of vulnerability in the glycan cap and detail mechanisms of action, including structural mimicry, trimer instability, and blocking cleavage.<br />Graphical Abstract

Details

Language :
English
ISSN :
22111247
Volume :
35
Issue :
2
Database :
OpenAIRE
Journal :
Cell Reports
Accession number :
edsair.doi.dedup.....7f4aad3cf89c598ab3f5717c47dbd873