5tdl
From Proteopedia
Crystal structure of prefusion-stabilized bovine RSV fusion glycoprotein (single-chain DS2-v1 variant: strain 391-2 sc9 DS-Cav1 Q98C Q361C)
Structural highlights
Function[FUS_BRSVC] During virus entry, induces fusion of viral and cellular membranes leading to delivery of the nucleocapsid into the cytoplasm. The fusogenic activity is inactive untill entry into host cell endosome, where a furin-like protease cleaves off a small peptide between F1 and F2. Interacts directly with heparan sulfate and may participate in virus attachment. Later in infection, proteins F expressed at the plasma membrane of infected cells can mediate fusion with adjacent cells to form syncytia, a cytopathic effect that could lead to tissue necrosis. The fusion protein is also able to trigger p53-dependent apoptosis.[UniProtKB:P03420] Publication Abstract from PubMedBovine respiratory syncytial virus, a major cause of respiratory disease in calves, is closely related to human RSV, a leading cause of respiratory disease in infants. Recently, promising human RSV-vaccine candidates have been engineered that stabilize the metastable fusion (F) glycoprotein in its prefusion state; however, the absence of a relevant animal model for human RSV has complicated assessment of these vaccine candidates. Here, we use a combination of structure-based design, antigenic characterization, and X-ray crystallography to translate human RSV F stabilization into the bovine context. A "DS2" version of bovine respiratory syncytial virus F with subunits covalently fused, fusion peptide removed, and pre-fusion conformation stabilized by cavity-filling mutations and intra- and inter-protomer disulfides was recognized by pre-fusion-specific antibodies, AM14, D25, and MPE8, and elicited bovine respiratory syncytial virus-neutralizing titers in calves >100-fold higher than those elicited by post-fusion F. When challenged with a heterologous bovine respiratory syncytial virus, virus was not detected in nasal secretions nor in respiratory tract samples of DS2-immunized calves; by contrast bovine respiratory syncytial virus was detected in all post-fusion- and placebo-immunized calves. Our results demonstrate proof-of-concept that DS2-stabilized RSV F immunogens can induce highly protective immunity from RSV in a native host with implications for the efficacy of prefusion-stabilized F vaccines in humans and for the prevention of bovine respiratory syncytial virus in calves. Protection of calves by a prefusion-stabilized bovine RSV F vaccine.,Zhang B, Chen L, Silacci C, Thom M, Boyington JC, Druz A, Joyce MG, Guzman E, Kong WP, Lai YT, Stewart-Jones GBE, Tsybovsky Y, Yang Y, Zhou T, Baxa U, Mascola JR, Corti D, Lanzavecchia A, Taylor G, Kwong PD NPJ Vaccines. 2017 Mar 8;2:7. doi: 10.1038/s41541-017-0005-9. PMID:29021918[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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