Structure of West Nile Virus

Mukhopadhyay, Suchetana; Kim, Bong-Suk; Chipman, Paul R.; Rossmann, Michael G.; Kühn, Richard

doi:10.1126/science.1089316

Cited by 329 publications

(263 citation statements)

References 6 publications

Supporting

Mentioning

256

Contrasting

Order By: Relevance

“…Three-dimensional cryo-electron microscopy (cryo-EM) structures of the mature ZIKV particles have recently been reported to near atomic resolution (3.8 Å) 4,5 , showing that the virus has essentially the same organization as the other flaviviruses of known structure, such as dengue virus (DENV) 3 and West Nile virus 6,7 . The E protein is about 500 amino acids long, with the 400 N-terminal residues forming the ectodomain essentially folded as β-sheets with three domains, named I, II and III, aligned in a row with domain I at the centre.…”

mentioning

confidence: 99%

Structural basis of potent Zika–dengue virus antibody cross-neutralization

Barba-Spaeth

Dejnirattisai

Rouvinski

et al. 2016

Nature

468

516

View full text Add to dashboard Cite

Zika virus (ZIKV) is an arthropod-borne enveloped virus belonging to the Flavivirus genus in the family Flaviviridae, which also includes the human pathogenic yellow fever, dengue, West Nile and tick-borne encephalitis viruses 1 . Flaviviruses have two structural glycoproteins, prM and E (for precursor membrane and envelope proteins, respectively), which form a heterodimer in the endoplasmic reticulum (ER) of the infected cell and drive the budding of spiky immature virions into the ER lumen. These particles transit through the cellular secretory pathway, during which the trans-Golgi-resident protease furin cleaves prM. This processing is required for infectivity, and results in the loss of a large fragment of prM and reorganization of E on the virion surface. The mature particles have a smooth aspect, with 90 E dimers organized with icosahedral symmetry in a 'herringbone' pattern 2,3 .Three-dimensional cryo-electron microscopy (cryo-EM) structures of the mature ZIKV particles have recently been reported to near atomic resolution (3.8 Å) 4,5 , showing that the virus has essentially the same organization as the other flaviviruses of known structure, such as dengue virus (DENV) 3 and West Nile virus 6,7 . The E protein is about 500 amino acids long, with the 400 N-terminal residues forming the ectodomain essentially folded as β-sheets with three domains, named I, II and III, aligned in a row with domain I at the centre. The conserved fusion loop is at the distal end of the rod in domain II, buried at the E dimer interface. At the C terminus, the E ectodomain is followed by the 'stem' , featuring two α-helices lying flat on the viral membrane (the stem helices), which link to two C-terminal transmembrane α-helices. The main distinguishing feature of the ZIKV virion is an insertion within a glycosylated loop of E (the '150' loop), which protrudes from the mature virion surface 4,5 .Flaviviruses have been grouped into serocomplexes based on cross-neutralization studies with polyclonal immune sera 8 . The E protein is the main target of neutralizing antibodies, and is also the viral fusogen; cleavage of prM allows E to respond to the endosomal pH by undergoing a large-scale conformational change that catalyses membrane fusion and releases the viral genome into the cyotosol. Loss of the precursor fragment of prM lets the E protein fluctuate from its tight packing at the surface of the virion, transiently exposing otherwise buried surfaces. One surface exposed by this 'breathing' is the fusionloop epitope (FLE), which is a dominant cross-reactive antigenic site 9 . Although antibodies to this site can protect by complement-mediated mechanisms, as shown in a mouse model for West Nile virus 10 , they are poorly neutralizing and lead to antibody-dependent enhancement 11-15 , thereby aggravating Flavivirus pathogenesis and complicating the development of safe and effective vaccines.We recently reported the functional and structural characterization of a panel of antibodies isolated from patients with dengue disease 13,16 . ...

show abstract

mentioning

confidence: 99%

Structural basis of potent Zika–dengue virus antibody cross-neutralization

Barba-Spaeth

Dejnirattisai

Rouvinski

et al. 2016

Nature

468

516

View full text Add to dashboard Cite

show abstract

“…The three E monomers per icosahedral asymmetric unit each have distinctly different environments (5,6), contrary to most other icosahedral viruses in which all subunits have at least quasi-similar environments. The ectodomain of E consists of three structural domains, DI, DII, and DIII (7)(8)(9).…”

Section: W Est Nile Virus (Wnv) Causes a Febrile Illness In Humansmentioning

confidence: 87%

West Nile virus in complex with the Fab fragment of a neutralizing monoclonal antibody

Kaufmann

Nybakken

Chipman

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

119

122

View full text Add to dashboard Cite

Flaviviruses, such as West Nile virus (WNV), are significant human pathogens. The humoral immune response plays an important role in the control of flavivirus infection and disease. The structure of WNV complexed with the Fab fragment of the strongly neutralizing mAb E16 was determined to 14.5-Å resolution with cryoelectron microscopy. E16, an antibody with therapeutic potential, binds to domain III of the WNV envelope glycoprotein. Because of steric hindrance, Fab E16 binds to only 120 of the 180 possible binding sites on the viral surface. Fitting of the previously determined x-ray structure of the Fab-domain III complex into the cryo-electron microscopy density required a change of the elbow angle between the variable and constant domains of the Fab. The structure suggests that the E16 antibody neutralizes WNV by blocking the initial rearrangement of the E glycoprotein before fusion with a cellular membrane.cryo-electron microscopy ͉ flavivirus ͉ neutralization W est Nile virus (WNV) causes a febrile illness in humans that can progress to encephalitis, paralysis, and death. Although endemic in parts of Africa, Asia, Europe, and the Middle East, it was first isolated in the United States in 1999 and has subsequently spread throughout North America and the Caribbean (1-3). The similar Kunjin virus is found in Australia (4). WNV, a member of the Flaviviridae family, is closely related to other arthropod-borne, medically important viruses, such as dengue, yellow fever, Japanese encephalitis, and tick-borne encephalitis viruses. These small, Ϸ500-Å-diameter, lipidenveloped viruses enter their host cells by receptor-mediated endocytosis. A low pH-triggered conformational rearrangement of the viral surface glycoproteins resulting in a fusion-active state of the virion allows the release of the single-stranded, positivesense RNA genome from the endosomes into the cytoplasm.The outer surface of mature infectious particles is formed by an icosahedral scaffold of 90 homodimers of the membraneanchored envelope glycoprotein (E). The three E monomers per icosahedral asymmetric unit each have distinctly different environments (5, 6), contrary to most other icosahedral viruses in which all subunits have at least quasi-similar environments. The ectodomain of E consists of three structural domains, DI, DII, and DIII (7-9). DI is structurally positioned between DII and DIII. The dimerization DII contains a 12-residue-long loop essential for virus-cell membrane fusion and, in dengue virus, has carbohydrate moieties that mediate receptor binding (10). The C-terminal DIII undergoes a major, pH-triggered, positional rearrangement essential for fusion and may also be involved in receptor binding (7,(11)(12)(13)(14)(15)(16)(17)(18).The humoral immune response is crucial for protection against flavivirus infection and disease (19). Antibodies can prevent infection by interference with functions mediated by viral surface proteins, such as receptor attachment, virus internalization, and membrane fusion. Indeed, the E glycoprotein is the...

show abstract

“…The structure of WNV particles have been elucidated by Mukhopadhay et al [6]. Electron microscopy and image reconstruction techniques established that WNV is a small spherical icosahedral virus with a 50 nm diameter and a lipid envelope surrounding an icosahedral nucleocapsid consisting of capsid proteins that are associated with the RNA genome (Figure 1a).…”

Section: West Nile Virusmentioning

confidence: 99%

Recent progress in West Nile virus diagnosis and vaccination

Filette

Ulbert

Diamond

et al. 2012

Vet Res

132

View full text Add to dashboard Cite

West Nile virus (WNV) is a positive-stranded RNA virus belonging to the Flaviviridae family, a large family with 3 main genera (flavivirus, hepacivirus and pestivirus). Among these viruses, there are several globally relevant human pathogens including the mosquito-borne dengue virus (DENV), yellow fever virus (YFV), Japanese encephalitis virus (JEV) and West Nile virus (WNV), as well as tick-borne viruses such as tick-borne encephalitis virus (TBEV). Since the mid-1990s, outbreaks of WN fever and encephalitis have occurred throughout the world and WNV is now endemic in Africa, Asia, Australia, the Middle East, Europe and the Unites States. This review describes the molecular virology, epidemiology, pathogenesis, and highlights recent progress regarding diagnosis and vaccination against WNV infections.

show abstract

Structure of West Nile Virus

Cited by 329 publications

References 6 publications

Structural basis of potent Zika–dengue virus antibody cross-neutralization

Structural basis of potent Zika–dengue virus antibody cross-neutralization

West Nile virus in complex with the Fab fragment of a neutralizing monoclonal antibody

Recent progress in West Nile virus diagnosis and vaccination

Contact Info

Product

Resources

About