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Structural basis for antibody inhibition of flavivirus NS1-triggered endothelial dysfunction. | LitMetric

AI Article Synopsis

  • Medically important flaviviruses, such as dengue, Zika, and West Nile virus, cause significant global health issues, with their nonstructural protein 1 (NS1) playing a key role in disease development.
  • Researchers present three crystal structures of the dengue virus NS1 protein, captured with a specific monoclonal antibody (2B7), revealing how this antibody can inhibit NS1's harmful effects.
  • The study highlights that the NS1 protein's distinct domains are crucial for binding to cells and triggering pathological outcomes, suggesting that targeting NS1 with antibodies like 2B7 could offer a broad treatment strategy for infections caused by various flaviviruses.

Article 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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8000976PMC
http://dx.doi.org/10.1126/science.abc0476DOI Listing

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