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

Journal Article · Sun Feb 01 00:00:00 EST 2015 · Cell

DOI:https://doi.org/10.1016/j.cell.2015.01.041· OSTI ID:1239608

Hashiguchi, Takao; Fusco, Marnie L.; Bornholdt, Zachary A.; Lee, Jeffrey E.; Flyak, Andrew I.; Matsuoka, Rei; Kohda, Daisuke; Yanagi, Yusuke; Hammel, Michal; Crowe, Jr., James E.; Saphire, Erica Ollmann

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. We find that 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.

• Research Organization: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
• Sponsoring Organization: USDOE
• Grant/Contract Number: U19 AI109762; R01 AI089498; R21AI069347; HDTRA1-13-1-0034; U19 AI109711; 26713018; 24115005; MINOS GM105404
• OSTI ID: 1239608
• Alternate ID(s): OSTI ID: 1233887; OSTI ID: 1257826
• Journal Information: Cell, Journal Name: Cell Vol. 160 Journal Issue: 5; ISSN 0092-8674
• Publisher: Elsevier
• Country of Publication: United States
• Language: English

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59 BASIC BIOLOGICAL SCIENCES