Creatine kinase (CK) is an enzyme involved in the regulation of energy levels in the cell. It has clinically important functions in the cardiovascular system and is being investigated in association with development, hormone regulation of a range of physiological functions, and disease states ranging from neuromuscular disorders to cancer. We are studying its structure-function relationships. We are using two structures of creatine kinases and one of a homolog, arginine kinase, to better interpret the structure-function relationships in CK and other guanidino kinases and require the resources of the Computer Graphics Laboratory to visualize and compare these structures. We build models to reflect structural differences among the CK isoenzymes and use those models to help us understand how these forms evolved to interact with different cellular structures. Integration of structural and mechanistic information in this fashion reflects the major focus of our studies. The Computer Graphics Laboratory is central to the development of this line of inquiry. This system also serves as a model system for development of new computational tools to model structure-function relationships in collaboration with investigators outside of UCSF. Again, the CGL is critical to this effort and we plan collaborations with CGL staff to help us develop these tools for general use. We are currently using some new tools in development at CGL (MSFviewer and the associated superposition software, RmsMin) to map differences in specificity of CK isozyme sequences to the structural templates that are presently available. This exercise has helped us to predict additional putative active site residues initially identified from inverse folding computational experiments.
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