Structural characterization of respiratory syncytial virus fusion inhibitor escape mutants: homology model of the F protein and a syncytium formation assay

Respiratory syncytial virus (RSV) is a ubiquitous human pathogen and the leading cause of lower respiratory tract infections in infants. Infection of cells and subsequent formation of syncytia occur through membrane fusion mediated by the RSV fusion protein (RSV-F). A novel in vitro assay of recombi...

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Bibliographic Details
Published in:Virology (New York, N.Y.) N.Y.), 2003-07, Vol.311 (2), p.275-288
Main Authors: Morton, Craig J, Cameron, Rachel, Lawrence, Lynne J, Lin, Bo, Lowe, Melinda, Luttick, Angela, Mason, Anthony, McKimm-Breschkin, Jenny, Parker, Michael W, Ryan, Jane, Smout, Michael, Sullivan, Jayne, Tucker, Simon P, Young, Paul R
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Animals
Antiviral
Antiviral Agents - pharmacology
Assay
Binding Sites, Antibody
Cell Line
Fusion protein
Giant Cells - virology
Homology model
Inhibitor
Models, Molecular
Molecular Sequence Data
Mutation - genetics
Protein Conformation
Respiratory syncytial virus
Respiratory Syncytial Viruses - genetics
Respiratory Syncytial Viruses - metabolism
Sequence Alignment
Viral Fusion Proteins - antagonists & inhibitors
Viral Fusion Proteins - chemistry
Viral Fusion Proteins - genetics
Viral Fusion Proteins - ultrastructure
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Summary:Respiratory syncytial virus (RSV) is a ubiquitous human pathogen and the leading cause of lower respiratory tract infections in infants. Infection of cells and subsequent formation of syncytia occur through membrane fusion mediated by the RSV fusion protein (RSV-F). A novel in vitro assay of recombinant RSV-F function has been devised and used to characterize a number of escape mutants for three known inhibitors of RSV-F that have been isolated. Homology modeling of the RSV-F structure has been carried out on the basis of a chimera derived from the crystal structures of the RSV-F core and a fragment from the orthologous fusion protein from Newcastle disease virus (NDV). The structure correlates well with the appearance of RSV-F in electron micrographs, and the residues identified as contributing to specific binding sites for several monoclonal antibodies are arranged in appropriate solvent-accessible clusters. The positions of the characterized resistance mutants in the model structure identify two promising regions for the design of fusion inhibitors.
ISSN:0042-6822
1096-0341
DOI:10.1016/S0042-6822(03)00115-6