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

By Charles D Murin, Pavlo Gilchuk, Philipp Ilinykh, Kai Huang, Natalia Kuzmina, Xiaoli Shen, Jessica F Brunh, Aubrey L Brunh, Edgar Davidson, Benjamin Doranz, Lauren E Williamson, Jeffrey Copps, Tanwee Alkutkar, Andrew I Flyak, Alexander Bukreyev, James E. Crowe, Andrew B. Ward

Posted 14 Oct 2020
bioRxiv DOI: 10.1101/2020.10.14.340026

Antibodies that target the glycan cap epitope on 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 is not well-understood. Here we present cryo-electron microscopy (cryo-EM) structures of several 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 (MLD) to the glycan cap, which we name the MLD-anchor and cradle. Antibodies that bind to the MLD-cradle share common features, including the use of IGHV1-69 and IGHJ6 germline genes, which exploit hydrophobic residues and form beta-hairpin structures to mimic the MLD-anchor, disrupt MLD attachment, destabilize GP quaternary structure and block cleavage events required for receptor binding. Our results collectively provide a molecular basis for ebolavirus neutralization by broadly reactive glycan cap antibodies. ### Competing Interest Statement A.L.B., E.D., and B.J.D. are employees of Integral Molecular. B.J.D. is a shareholder of Integral Molecular. J.E.C. has served as a consultant for Sanofi and is on the Scientific Advisory Boards of CompuVax and Meissa Vaccines, is a recipient of previous unrelated research grants from Moderna and Sanofi and is founder of IDBiologics. Vanderbilt University has applied for a patent that is related to this work. All other authors declare no competing interests.

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