Convergence of a common solution for broad ebolavirus neutralization by glycan cap-directed human antibodies
Charles D. Murin,
Pavlo Gilchuk,
Philipp A. Ilinykh,
Kai Huang,
Natalia Kuzmina,
Xiaoli Shen,
Jessica F. Bruhn,
Aubrey L. Bryan,
Edgar Davidson,
Benjamin J. Doranz,
Lauren E. Williamson,
Jeffrey Copps,
Tanwee Alkutkar,
Andrew I. Flyak,
Alexander Bukreyev,
James E. Crowe, Jr.,
Andrew B. Ward
Affiliations
Charles D. Murin
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA
Pavlo Gilchuk
Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA
Philipp A. Ilinykh
Galveston National Laboratory, Galveston, TX 77550, USA; Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USA
Kai Huang
Galveston National Laboratory, Galveston, TX 77550, USA; Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USA
Natalia Kuzmina
Galveston National Laboratory, Galveston, TX 77550, USA; Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USA
Xiaoli Shen
Galveston National Laboratory, Galveston, TX 77550, USA; Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USA
Jessica F. Bruhn
Laboratory of Genetics and Helmsley Center for Genomic Medicine, The Salk Institute for Biological Sciences, La Jolla, CA 92037, USA
Aubrey L. Bryan
Integral Molecular, Inc., Philadelphia, PA 19104, USA
Edgar Davidson
Integral Molecular, Inc., Philadelphia, PA 19104, USA
Benjamin J. Doranz
Integral Molecular, Inc., Philadelphia, PA 19104, USA
Lauren E. Williamson
Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
Jeffrey Copps
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA
Tanwee Alkutkar
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA
Andrew I. Flyak
Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
Alexander Bukreyev
Galveston National Laboratory, Galveston, TX 77550, USA; Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USA; Department of Microbiology & Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA
James E. Crowe, Jr.
Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232, USA
Andrew B. Ward
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA; Corresponding author
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.
