Trimeric coiled-coils as viral fusion protein mimics
Date
2008
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Abstract
α-Helical coiled-coils, a protein structural motif formed by supercoiling of two or more component polypeptide strands, are ubiquitous mediators of biological structure and function. Their characteristic primary heptad repeat, denoted abcdefg, makes these complexes attractive scaffolds for studying self-assembly and molecular recognition. Assembly of these structures is driven by the hydrophobic effect in which the hydrophobic sidechains associated with positions a and d are specifically packed together. Recently we have described methods for controlling the assembly of 1:1:1 heterotrimeric coiled-coils using only interior hydrophobic core residues. These core residues assemble according to steric matching, one large sidechain packs against two small sidechains. In the following text we have explored new sidechain parings. This steric matching strategy affords maximal sequence flexibility in the patterning of exterior surface residues, which we have exploited to create mimics of therapeutically significant protein-protein interfaces. The Human Immunodeficiency Virus (HIV) envelope protein gp41 facilitates infection by promoting fusion of cellular and viral membranes. At the heart of its function is formation of a trimer-of-hairpins structure in which a C-terminal ligand peptide binds to an N-terminal coiled-coil surface. This interaction is reminiscent of those in numerous other viral systems, including visna, the sheep analog of HIV. The design of protein mimics for viral systems by installation of key contact residues onto heterotrimer coiled-coils will be further discussed. The following text will highlight the structural verification of these mimics through various spectroscopic techniques. Also the validation of these mimics will be tested by exposure to known viral inhibitors. The work included in this text builds on previous research conducted in our laboratory, but it provides new avenues for future projects to explore the detailed interactions within the viral fusion mimics. This will hopefully lead to a better understanding of the viruses being studied as well as the underlying molecular interactions taking place.
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Subject
coiled-coils
fusion protein mimics
fusion proteins
HIV
organic chemistry
virology