STRUCTURAL STUDIES OF HUMAN NTP-BINDING PROTEINS

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. NTP-binding proteins, such as kinases and ATPases, are important effectors of biological activity in both prokaryotes and eukaryotes. Because of this, they serve as nodes for therapeutic intervention and are thus critical drug targets. In the following experimental program we propose to perform structural studies on several key human NTP-binding proteins to further elucidate their mechanism of function as well as to integrate these proteins into an iterative structure-based drug design cycle. An iterative structure-based drug design cycle typically begins by solving the structure of the drug target by X-ray crystallography; this structure and numerous drug target:lead compound (target:ligand) co-structures are used in combination with molecular modeling and medicinal chemistry to synthesize lead compounds with improved potency and other improved characteristics. The cycle is continued until all compound optimization is completed. A rapid turn-around time is critical to the cycle and thus synchrotron data collection is of paramount importance. Our goal is to perform structural studies and iterative structure-based drug design on 7 projects: human AKT3, human CSF1R, human EG5, human HSP90, human PDK1, human PI3 kinase (both alpha and gamma isoforms), and various human receptor tyrosine kinases. The purpose of these studies will be to understand the mechanism of action of these enzymes, as well as to integrate each into a structure-based drug design cycle.