期刊
SCIENCE
卷 371, 期 6525, 页码 194-+出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.abc0476
关键词
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资金
- NIAID/NIH [R01 AI24493, R21 AI146464, U19 AI109761, R56 AI130130]
- NIH [5U24AI116833-02]
- Bill and Melinda Gates Foundation [OPP1155863]
- Value of Vaccine Research Network grant
- Life Sciences Research Foundation
- Bill and Melinda Gates Foundation [OPP1155863] Funding Source: Bill and Melinda Gates Foundation
The study revealed a protective mechanism by simultaneously antagonizing two domains of NS1, providing a mechanistic explanation for 2B7 protection against NS1-induced pathology and demonstrating the potential of this antibody to treat infections by multiple flaviviruses.
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 beta-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.
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