This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.While several segments of HIV integrase are available in the Protein Data Bank, experimental structures of intact full-length integrase in its catalytically relevant oligomeric states and integrase-DNA complex have eluded crystallographic analysis. The goal of this study is to develop experimentally-derived models of these macromolecular complexes, which is vital to advancing our understanding of HIV integration and its structural basis. The ongoing AIDS pandemic has made the design of effective pharmacological treatments a goal of paramount importance. While some promising integrase inhibitors are emerging from late clinical trials, most available inhibitors in clinical use only target other viral-encoded proteins. Because integration of viral cDNA into the host genome is critical to the retroviral life cycle and since there are no known cellular enzymes that closely resemble integrase in sequence or function, inhibitors of integrase have the potential to be relatively nontoxic and very effective. It is now clear that, in comparison to free integrase in solution, correctly assembled integrase complex has a different and more discriminating response to inhibitors. Hence, a detailed structural model of the complex is essential to structure-based drug design. Biophysical characterization of complexes formed by HIV integrase, the integrase-binding protein Lens Epithelial-Derived Growth Factor (LEDGF), and DNA substrate, using analytical ultracentrifugation and gel filtration, has already been completed. Pilot SAXS experiments at Beamline G1 of CHESS have already been performed at a limited range of sample concentrations.
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