The lifecycle of HIV-1 is intimately associated with membranes. The virus particles have a membrane envelope that contains structural proteins responsible for recognition and fusion with susceptible cells, and the final step of viral reproduction involves the budding out of new virus particles from the membrane of infected cells. Vpu is a small (81 residue) HIV-1 accessory protein with two biological functions. It enhances the degradation of CD4/gp160 complexes, enabling gp160 to be processed to form the gp41 and gp120 proteins required for the formation of new virus particles, and it facilitates the budding out of new virus particles, perhaps through its ion channel activity. Structural biology is based on the premise that in order to understand how protein express their biological functions it is essential to determine their structures. And this is certainly the case for Vpu where its biological activities appear to be associated with different regions of the protein structure. However, membrane protein like Vpu present extraordinary technical challenges for structural biology, largely because the principal experimental methods were developed for soluble, globular proteins rather than hydrophobic proteins in lipid environments. The overall goal of this Program Project is to develop experimental and theoretical methods for determining the structures and describing the dynamics of membrane proteins and to apply these method to Vpu. The most powerful approaches to structural biology will be brought to bear on Vpu as a model membrane protein and an important target for antiviral drug development, including NMR spectroscopy, x-ray crystallography, molecular dynamics simulations, and neutron diffraction. The structural results will be integrated with the functional analysis of Vpu as an ion channel. The combination of structural and functional information about Vpu will be used to develop drugs that interfere with its functions.
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