Structural basis for antibody inhibition of flavivirus NS1-triggered endothelial dysfunction.
Science
; 371(6525): 194-200, 2021 01 08.
Article
en En
| MEDLINE
| ID: mdl-33414220
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 ß-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.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Virus del Nilo Occidental
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Proteínas no Estructurales Virales
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Virus del Dengue
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Anticuerpos Neutralizantes
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Virus Zika
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Anticuerpos Antivirales
Límite:
Animals
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Humans
Idioma:
En
Año:
2021
Tipo del documento:
Article