The flavivirus envelope protein E: isolation of a soluble form from tick-borne encephalitis virus and its crystallization

Heinz, Franz X.; Mandl, Christian W.; Holzmann, Heidemarie; Künz, Christian; Harris, Bruce A.; Rey, F.A.; Harrison, S.

doi:10.1128/jvi.65.10.5579-5583.1991

Cited by 63 publications

(19 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Truncated sE dimers were produced as described previously (36). Briefly, purified TBE virus was treated with trypsin at 0°C, the residual particles were removed by ultracentrifugation, and the sE dimers were purified by anionexchange chromatography.…”

Section: Methodsmentioning

confidence: 99%

Cryptic Properties of a Cluster of Dominant Flavivirus Cross-Reactive Antigenic Sites

Stiasny

Kiermayr

Holzmann

et al. 2006

J Virol

210

243

View full text Add to dashboard Cite

A number of flaviviruses are important human pathogens, including yellow fever, dengue, West Nile, Japanese encephalitis, and tick-borne encephalitis (TBE) viruses. Infection with or immunization against any of these viruses induces a subset of antibodies that are broadly flavivirus cross-reactive but do not exhibit significant cross-neutralization. Nevertheless, these antibodies can efficiently bind to the major envelope protein (E), which is the main target of neutralizing and protective antibodies because of its receptor-binding and membrane fusion functions. The structural basis for this phenomenon is still unclear. In our studies with TBE virus, we have provided evidence that such cross-reactive antibodies are specific for a cluster of epitopes that are partially occluded in the cage-like assembly of E proteins at the surfaces of infectious virions and involve-but are not restricted to-amino acids of the highly conserved internal fusion peptide loop. Virus disintegration leads to increased accessibility of these epitopes, allowing the cross-reactive antibodies to bind with strongly increased avidity. The cryptic properties of these sites in the context of infectious virions can thus provide an explanation for the observed lack of efficient neutralizing activity of broadly cross-reactive antibodies, despite their specificity for a functionally important structural element in the E protein.

show abstract

Section: Methodsmentioning

confidence: 99%

Cryptic Properties of a Cluster of Dominant Flavivirus Cross-Reactive Antigenic Sites

Stiasny

Kiermayr

Holzmann

et al. 2006

J Virol

210

243

View full text Add to dashboard Cite

show abstract

“…E is a dimer on the surface of a mature virion (Heinz et al, 1991;Kuhn et al, 2002). Its stable (stemless) ectodomain ("soluble E" or sE, comprising domains I, II, and III-approximately 395 of the 450 residues that lie outside the viral membrane) is also a dimer in solution at reasonable concentrations (Heinz et al, 1991). The fusion loop at the tip of domain II lies at the dimer interface, sequestered from potential membrane insertions until lowered pH triggers rearrangement (Rey et al, 1995).…”

Section: A Flavivirusesmentioning

confidence: 99%

Mechanism of Membrane Fusion by Viral Envelope Proteins

Harrison

2005

Advances in Virus Research

179

191

View full text Add to dashboard Cite

“…Only a few examples of viral entry inhibitors with activity against the primarily beta sheet envelope proteins (E) from flaviviruses have been described [8][9][10]. However, few of these have taken advantage of the available crystal structures of flavivirus E proteins, including both pre-fusion and post-fusion forms [11][12][13][14][15][16][17][18][19][20][21][22]. The authors of some of these structures have predicted that several regions of these proteins might be targets for inhibition [11,14,15].…”

Section: Introductionmentioning

confidence: 99%

Structural Optimization and De Novo Design of Dengue Virus Entry Inhibitory Peptides

et al. 2010

View full text Add to dashboard Cite

Viral fusogenic envelope proteins are important targets for the development of inhibitors of viral entry. We report an approach for the computational design of peptide inhibitors of the dengue 2 virus (DENV-2) envelope (E) protein using high-resolution structural data from a pre-entry dimeric form of the protein. By using predictive strategies together with computational optimization of binding “pseudoenergies”, we were able to design multiple peptide sequences that showed low micromolar viral entry inhibitory activity. The two most active peptides, DN57opt and 1OAN1, were designed to displace regions in the domain II hinge, and the first domain I/domain II beta sheet connection, respectively, and show fifty percent inhibitory concentrations of 8 and 7 µM respectively in a focus forming unit assay. The antiviral peptides were shown to interfere with virus:cell binding, interact directly with the E proteins and also cause changes to the viral surface using biolayer interferometry and cryo-electron microscopy, respectively. These peptides may be useful for characterization of intermediate states in the membrane fusion process, investigation of DENV receptor molecules, and as lead compounds for drug discovery.

show abstract

The flavivirus envelope protein E: isolation of a soluble form from tick-borne encephalitis virus and its crystallization

Cited by 63 publications

References 31 publications

Cryptic Properties of a Cluster of Dominant Flavivirus Cross-Reactive Antigenic Sites

Cryptic Properties of a Cluster of Dominant Flavivirus Cross-Reactive Antigenic Sites

Mechanism of Membrane Fusion by Viral Envelope Proteins

Structural Optimization and De Novo Design of Dengue Virus Entry Inhibitory Peptides

Contact Info

Product

Resources

About