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

Science. 2021 Jan 8;371(6525):194-200. doi: 10.1126/science.abc0476.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / chemistry
  • Antibodies, Monoclonal / immunology
  • Antibodies, Neutralizing / chemistry*
  • Antibodies, Neutralizing / immunology
  • Antibodies, Viral / chemistry*
  • Antibodies, Viral / immunology
  • Cross Reactions
  • Crystallography, X-Ray
  • Dengue / prevention & control
  • Dengue / therapy
  • Dengue Virus / immunology*
  • Endothelium / immunology
  • Glycocalyx / immunology
  • Humans
  • Mice
  • Protein Conformation, beta-Strand
  • Protein Domains
  • Viral Nonstructural Proteins / chemistry
  • Viral Nonstructural Proteins / immunology*
  • West Nile Fever / prevention & control
  • West Nile Fever / therapy
  • West Nile virus / immunology*
  • Zika Virus / immunology*
  • Zika Virus Infection / prevention & control
  • Zika Virus Infection / therapy


  • Antibodies, Monoclonal
  • Antibodies, Neutralizing
  • Antibodies, Viral
  • NS1 protein, Flavivirus
  • Viral Nonstructural Proteins