5TDL

Crystal structure of prefusion-stabilized bovine RSV fusion glycoprotein (single-chain DS2-v1 variant: strain 391-2 sc9 DS-Cav1 Q98C Q361C)

Summary for 5TDL

• Entry DOI: 10.2210/pdb5tdl/pdb
• Related: 5tdg
• Descriptor: Bovine prefusion RSV F glycoprotein, 2-acetamido-2-deoxy-beta-D-glucopyranose (2 entities in total)
• Functional Keywords: bovine rsv f, pre-fusion stabilized, single chain, viral protein
• Biological source: Bovine respiratory syncytial virus (strain Copenhagen) (BRS); More
• Total number of polymer chains: 1
• Total formula weight: 59223.56

Authors

Chen, L.,Zhang, B.,Kwong, P.D. (deposition date: 2016-09-19, release date: 2017-08-16, Last modification date: 2020-07-29)

Primary citation

Zhang, B.,Chen, L.,Silacci, C.,Thom, M.,Boyington, J.C.,Druz, A.,Joyce, M.G.,Guzman, E.,Kong, W.P.,Lai, Y.T.,Stewart-Jones, G.B.E.,Tsybovsky, Y.,Yang, Y.,Zhou, T.,Baxa, U.,Mascola, J.R.,Corti, D.,Lanzavecchia, A.,Taylor, G.,Kwong, P.D.
Protection of calves by a prefusion-stabilized bovine RSV F vaccine.
NPJ Vaccines, 2:7-7, 2017

PubMed Abstract: Bovine 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.

PubMed: 29021918
DOI: 10.1038/s41541-017-0005-9

Experimental method

X-RAY DIFFRACTION (3.5 Å)