Convergence of a common solution for broad ebolavirus neutralization by glycan cap-directed human antibodies
| Autor: | 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 |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Models
Molecular 0301 basic medicine Antibodies Viral medicine.disease_cause Epitope Neutralization Epitopes Jurkat Cells Mice Ebola virus 0302 clinical medicine Viral Envelope Proteins Antibody Specificity antibody Biology (General) antibody therapeutics chemistry.chemical_classification biology Antibodies Monoclonal Ebolavirus Female Antibody Protein Binding Glycan filoviruses medicine.drug_class QH301-705.5 Computational biology Monoclonal antibody complex mixtures Article General Biochemistry Genetics and Molecular Biology 03 medical and health sciences Polysaccharides glycan cap medicine Animals Humans Protein Interaction Domains and Motifs Amino Acid Sequence Binding Sites Sequence Homology Amino Acid Cryoelectron Microscopy ebolaviruses Hemorrhagic Fever Ebola Antibodies Neutralizing HEK293 Cells 030104 developmental biology chemistry biology.protein Protein Conformation beta-Strand Protein quaternary structure Glycoprotein Sequence Alignment 030217 neurology & neurosurgery HeLa Cells |
| Zdroj: | Cell Reports, Vol 35, Iss 2, Pp 108984-(2021) Cell reports |
| ISSN: | 2211-1247 |
| Popis: | 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. 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. Graphical Abstract |
| Databáze: | OpenAIRE |
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