FRAGMENT BASED DRUG DISCOVERY TARGETING HIV PROTEASE

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Type IV pili (T4P) are key virulence factors for many bacterial pathogens, mediating a broad range of functions including surface motility, microcolony formation, adhesion, phage attachment and natural transformation. Type IV pili are of great scientific interest due to the central role these filaments play in bacterial pathogenesis and for their potential as targets for antibacterial interventions. Furthermore, from a biophysical standpoint, the pilus assembly apparatus represents a remarkable and unique molecular motor. We are working to solve the crystal structures of the components of the inner membrane platform of the Type IV pilus assembly apparatus. These data will be combined with structural data obtained from solid state NMR, electron microscopy, mutational analysis and biochemistry to obtain a detailed understanding of this critical molecular machine. This work will likely contribute to the design of new antibacterial therapies and to our understanding of another critical bacterial virulence system, the Type 2 secretion, which is highly similar to Type IV pilus system.