Structural basis for antibody inhibition of flavivirus NS1–triggered endothelial dysfunction
- 8 January 2021
- journal article
- research article
- Published by American Association for the Advancement of Science (AAAS) in Science
- Vol. 371 (6525), 194-200
- https://doi.org/10.1126/science.abc0476
Abstract
Medically important flaviviruses cause diverse disease pathologies and collectively are responsible for a major global disease burden. A contributing factor to pathogenesis is secreted flavivirus nonstructural protein 1 (NS1). Despite demonstrated protection by NS1-specific antibodies against lethal flavivirus challenge, the structural and mechanistic basis remains unknown. Here, we present three crystal structures of full-length dengue virus NS1 complexed with a flavivirus–cross-reactive, NS1-specific monoclonal antibody, 2B7, at resolutions between 2.89 and 3.96 angstroms. These structures reveal a protective mechanism by which two domains of NS1 are antagonized simultaneously. The NS1 wing domain mediates cell binding, whereas the β-ladder triggers downstream events, both of which are required for dengue, Zika, and West Nile virus NS1–mediated endothelial dysfunction. These observations provide a mechanistic explanation for 2B7 protection against NS1-induced pathology and demonstrate the potential of one antibody to treat infections by multiple flaviviruses.Keywords
Funding Information
- Bill and Melinda Gates Foundation (OPP1155863)
- NIAID (R01 AI24493)
- NIAID (R56 AI130130)
- NIAID (R21 AI146464)
- NIAID (U19 AI109761)
- NIAID (5U24AI116833-02)
- Value of Vaccine Research Network
- Value of Vaccine Research Network
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