Structural Basis for Marburg Virus Neutralization by a Cross-Reactive Human Antibody

• Published in: Cell Vol. 160; no. 5; pp. 904 - 912
• Main Authors: Hashiguchi, Takao, Fusco, Marnie L., Bornholdt, Zachary A., Lee, Jeffrey E., Flyak, Andrew I., Matsuoka, Rei, Kohda, Daisuke, Yanagi, Yusuke, Hammel, Michal, Crowe, James E., Saphire, Erica Ollmann
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 26.02.2015; Elsevier
• Subjects: Amino Acid Sequence; Animals; antibodies; Antibodies, Monoclonal - chemistry; Antibodies, Monoclonal - metabolism; Antibodies, Neutralizing - chemistry; Antibodies, Neutralizing - immunology; Antibodies, Neutralizing - isolation & purification; Antibodies, Neutralizing - metabolism; Antibodies, Viral - chemistry; Antibodies, Viral - immunology; Antibodies, Viral - metabolism; Antigen-Antibody Complex - chemistry; BASIC BIOLOGICAL SCIENCES; binding sites; Cell Line; Cross Reactions; crystal structure; Crystallography, X-Ray; Drosophila; Ebolavirus; Ebolavirus - chemistry; epitopes; glycoproteins; Humans; Immunoglobulin Fab Fragments - chemistry; Immunoglobulin Fab Fragments - metabolism; immunotherapy; Marburg marburgvirus; Marburg Virus Disease - immunology; Marburgvirus - chemistry; Marburgvirus - genetics; Marburgvirus - immunology; Models, Molecular; Molecular Sequence Data; Mucins - chemistry; neutralization tests; Sequence Alignment; Viral Envelope Proteins - chemistry; Viral Envelope Proteins - metabolism; X-radiation
• ISSN: 0092-8674; 1097-4172; 1097-4172
• DOI: 10.1016/j.cell.2015.01.041

The filoviruses, including Marburg and Ebola, express a single glycoprotein on their surface, termed GP, which is responsible for attachment and entry of target cells. Filovirus GPs differ by up to 70% in protein sequence, and no antibodies are yet described that cross-react among them. Here, we present the 3.6 Å crystal structure of Marburg virus GP in complex with a cross-reactive antibody from a human survivor, and a lower resolution structure of the antibody bound to Ebola virus GP. The antibody, MR78, recognizes a GP1 epitope conserved across the filovirus family, which likely represents the binding site of their NPC1 receptor. Indeed, MR78 blocks binding of the essential NPC1 domain C. These structures and additional small-angle X-ray scattering of mucin-containing MARV and EBOV GPs suggest why such antibodies were not previously elicited in studies of Ebola virus, and provide critical templates for development of immunotherapeutics and inhibitors of entry. [Display omitted] •Structure of the Marburg virus GP bound by MR78, a cross-reactive human antibody•The epitope is conserved among filoviruses and is the likely receptor-binding site•The antibody-GP interaction mimics that made by the Ebola virus glycan cap•Mucin domain structure may cause mAbs to react to Ebola and Marburg differently The structures of Marburg virus glycoprotein in complex with a cross-reactive human antibody, as well as of the Ebola virus glycoprotein bound to the same antibody, reveal that there is a conserved epitope among filoviruses that overlaps with the putative receptor-binding site. These studies provide a map by which therapy with cross-reactive antibodies and inhibitors of entry could be developed.