We will apply the approaches of structural biology to the study of macromolecular structures and inter-molecular interactions to find new pharmacological avenues for the treatment of HIV infections. The first project period resulted in a 3.5angstroms structure for HIV Reverse Transcriptase (RT) complexed with a drug, and also gave novel insights regarding intramembrane protein interactions. Continuing work on RT will involve improvement and refinement of the structure, crystallographic studies of drug complexes, crosslinking studies aimed at probing transfer RNA interactions with the protein, and, when the problem becomes sufficiently refined, efforts at structure-based drug design enhancement. Additional work on rev will explore its structure and role in splicing. Studies of the HIV Integrase will begin with production and crystallization efforts, followed by crystallographic studies. Interactions of tat with the TAR sequence will be probed, principally exploiting NMR approaches. Oligomerization of the transmembrane domains of gp41 and of the influenza hemagglutinin will be studied to develop structural and functional understanding of such interactions and to establish high capacity screens for specific disruptive agents. Computational work will focus initially on the HIV-1 protease complexed with various inhibitors as an important end in itself and as a basis for new approaches to structure based drug design. A core facility will provide computational support for the crystallography, NMR, and drug design efforts.
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