FUNCTION ANALYSIS OF EUKARYOTIC PROTEIN KINASES AND PHOSPHO-REGULATORY SYSTEMS

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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. The human genome encodes just over 500 protein kinases. These enzymes regulate protein function by catalyzing the transfer of the gamma phosphate of ATP onto specific hydroxyl bearing side chains in target proteins. Protein phosphorylation influences protein function either by inducing conformational change or by promoting the formation of macromolecular assemblies. Aberrant protein kinase function arising from mutation or viral subversion mechanisms gives rise to cellular dysfunctions that underlie numerous human diseases. The ability to counteract aberrant protein kinase function through the use of small molecule therapeutics has validated the protein kinase as a drugable target. The pervasiveness of protein kinases as regulators of cellular biology, stems from a plasticity of structure that allows for the diversification of catalytic switching and substrate recognition mechanisms. To date only a small fraction of eukaryotic protein kinases have been structurally characterized. In my lab, we are seeking to uncover the structural basis for novel catalytic switching, substrate recognition and down-stream phospho-regulatory mechanisms. Our long-term goal is to make use of what we learn about protein kinases and phospho-regulatory systems to develop drugs to treat disease. Currently, my lab has x-ray crystallographic studies underway on 10 distinct protein kinase/phospho-regulatory systems. A partial list includes the RNA dependent protein kinase PKR, the polo family protein kinases, the NDR1 kinase regulator Mob1, the tumor suppresor F-box adapter protein Cdc4, and the phospho-inositide binding protein kinase Akt.