Reversible inhibition of the fusion activity of measles virus F protein by an engineered intersubunit disulfide bridge |
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Authors: | Lee Jin K Prussia Andrew Snyder James P Plemper Richard K |
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Affiliation: | Division of Infectious Diseases, Department of Pediatrics, Emory University School of Medicine, 520 Children's Center, 2015 Uppergate Drive, Atlanta, GA 30322, USA. |
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Abstract: | In search of target sites for the development of paramyxovirus inhibitors, we have engineered disulfide bridges to introduce covalent links into the prefusion F protein trimer of measles virus. F-Edm-452C/460C, predicted to bridge head and stalk domains of different F monomers, shows a high degree of proteolytic maturation and surface expression, predominantly as stable, dithiothreitol-sensitive trimers, but no fusion activity. Reduction of disulfide bridges partially restores activity. These findings underscore the importance of reversible intersubunit interactions between the stalk and head domains for F activity. Noncovalent small molecules mimicking this behavior may constitute a potent strategy for preventing paramyxovirus entry. |
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