1. Structural basis for antibody inhibition of flavivirus NS1-triggered endothelial dysfunction.
- Author
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Biering SB, Akey DL, Wong MP, Brown WC, Lo NTN, Puerta-Guardo H, Tramontini Gomes de Sousa F, Wang C, Konwerski JR, Espinosa DA, Bockhaus NJ, Glasner DR, Li J, Blanc SF, Juan EY, Elledge SJ, Mina MJ, Beatty PR, Smith JL, and Harris E
- Subjects
- Animals, Antibodies, Monoclonal chemistry, Antibodies, Monoclonal immunology, Antibodies, Neutralizing immunology, Antibodies, Viral immunology, Cross Reactions, Crystallography, X-Ray, Dengue prevention & control, Dengue therapy, Endothelium immunology, Glycocalyx immunology, Humans, Mice, Protein Conformation, beta-Strand, Protein Domains, Viral Nonstructural Proteins chemistry, West Nile Fever prevention & control, West Nile Fever therapy, Zika Virus Infection prevention & control, Zika Virus Infection therapy, Antibodies, Neutralizing chemistry, Antibodies, Viral chemistry, Dengue Virus immunology, Viral Nonstructural Proteins immunology, West Nile virus immunology, Zika Virus immunology
- 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., (Copyright © 2021, American Association for the Advancement of Science.)
- Published
- 2021
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