7K93

DENV2 NS1 in complex with neutralizing 2B7 single chain Fab variable region (scFv)

Summary for 7K93

• Entry DOI: 10.2210/pdb7k93/pdb
• Descriptor: Non-structural protein 1, 2B7 single chain fab variable region, 2-acetamido-2-deoxy-beta-D-glucopyranose (3 entities in total)
• Functional Keywords: flavivirus ns1, antibody, fab fragment, viral protein
• Biological source: Dengue virus 2; More
• Total number of polymer chains: 8
• Total formula weight: 278460.14

Authors

Akey, D.L.,Smith, J.L. (deposition date: 2020-09-28, release date: 2020-12-23, Last modification date: 2024-11-20)

Primary citation

Biering, S.B.,Akey, D.L.,Wong, M.P.,Brown, W.C.,Lo, N.T.N.,Puerta-Guardo, H.,Tramontini Gomes de Sousa, F.,Wang, C.,Konwerski, J.R.,Espinosa, D.A.,Bockhaus, N.J.,Glasner, D.R.,Li, J.,Blanc, S.F.,Juan, E.Y.,Elledge, S.J.,Mina, M.J.,Beatty, P.R.,Smith, J.L.,Harris, E.
Structural basis for antibody inhibition of flavivirus NS1-triggered endothelial dysfunction.
Science, 371:194-200, 2021

PubMed 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.

PubMed: 33414220
DOI: 10.1126/science.abc0476

Experimental method

X-RAY DIFFRACTION (2.89 Å)