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

doi:10.1126/science.abc0476

GSTDTAP > 气候变化

DOI	10.1126/science.abc0476
	Structural basis for antibody inhibition of flavivirus NS1–triggered endothelial dysfunction
	Scott B. Biering; David L. Akey; Marcus P. Wong; W. Clay Brown; Nicholas T. N. Lo; Henry Puerta-Guardo; Francielle Tramontini Gomes de Sousa; Chunling Wang; Jamie R. Konwerski; Diego A. Espinosa; Nicholas J. Bockhaus; Dustin R. Glasner; Jeffrey Li; Sophie F. Blanc; Evan Y. Juan; Stephen J. Elledge; Michael J. Mina; P. Robert Beatty; Janet L. Smith; Eva Harris
	2021-01-08
发表期刊	Science
出版年	2021
英文摘要	Flaviviruses are a group of RNA viruses that include the human pathogens dengue virus, Zika virus, and West Nile virus. The envelope protein (E) on the virus surface has been the target of vaccine development, but problems have arisen with antibodies against E, leading to enhanced infection. Now, Modhiran et al. and Biering et al. describe two different antibodies that bind to the flavivirus NS1 protein and prevent it from disrupting epithelial cells, which is associated with severe disease. Both antibodies cross-react with multiple flavivirus NS1 proteins. The antibodies reduce viremia and increase survival in mouse models of flavivirus disease. Both papers include structures of NS1 bound to an antibody, which give insight into the protective mechanism. Science , this issue p. [190][1], p. [194][2] 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. [1]: /lookup/doi/10.1126/science.abb9425 [2]: /lookup/doi/10.1126/science.abc0476
领域	气候变化 ; 资源环境
URL	查看原文
引用统计
文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/310453
专题	气候变化资源环境科学
推荐引用方式 GB/T 7714	Scott B. Biering,David L. Akey,Marcus P. Wong,等. Structural basis for antibody inhibition of flavivirus NS1–triggered endothelial dysfunction[J]. Science,2021.
APA	Scott B. Biering.,David L. Akey.,Marcus P. Wong.,W. Clay Brown.,Nicholas T. N. Lo.,...&Eva Harris.(2021).Structural basis for antibody inhibition of flavivirus NS1–triggered endothelial dysfunction.Science.
MLA	Scott B. Biering,et al."Structural basis for antibody inhibition of flavivirus NS1–triggered endothelial dysfunction".Science (2021).