PT - JOURNAL ARTICLE AU - Charles D. Murin AU - Pavlo Gilchuk AU - Philipp A. Ilinykh AU - Kai Huang AU - Natalia Kuzmina AU - Xiaoli Shen AU - Jessica F. Bruhn AU - Aubrey L. Bryan AU - Edgar Davidson AU - Benjamin J. Doranz AU - Lauren E. Williamson AU - Jeffrey Copps AU - Tanwee Alkutkar AU - Andrew I. Flyak AU - Alexander Bukreyev AU - James E. Crowe, Jr. AU - Andrew B. Ward TI - Convergence of a common solution to broad ebolavirus neutralization by glycan cap directed human antibodies AID - 10.1101/2020.10.14.340026 DP - 2020 Jan 01 TA - bioRxiv PG - 2020.10.14.340026 4099 - http://biorxiv.org/content/early/2020/10/14/2020.10.14.340026.short 4100 - http://biorxiv.org/content/early/2020/10/14/2020.10.14.340026.full AB - 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 StatementA.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.