National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)
U19 AI109762
米国
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)
U19 AI142785
米国
引用
ジャーナル: Cell Rep / 年: 2021 タイトル: Convergence of a common solution for broad ebolavirus neutralization by glycan cap-directed human antibodies. 著者: 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 / ...著者: 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 / Andrew B Ward / 要旨: 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 ...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.
Complex of Ebola virus GP (mucin deleted, Makona strain) bound to the antibody Fab EBOV-293 and EBOV-515
COMPLEX
Complex components were expressed in HEK 293F cells, complexed and purified by size exclusion chromatography. The Fab ADI-15878 was added to increase complex size and assist in angular sampling but was not build in the associated model.