RIG: Structure-Function Relationships in the Regulation of Human Liver Glucokinase by Glucokinase Regulatory Protein

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This research project involves the study of two proteins that are essential for the maintenance of stable blood glucose levels, glucokinase (GK) and its regulatory protein, glucokinase regulatory protein (GKRP). Biochemical analyses and X-ray crystallography will be used to delineate the structural basis for allostery in the negative regulation of GK by GKRP. The specific aims of this project are: (1) to determine the three-dimensional structure of rat liver GKRP in the presence of fructose-1-phosphate and in the presence of fructose-6-phosphate, (2) to use crystallographic data to model the necessary interactions and structural features required for formation of the GK/GKRP complex, and (3) to evaluate the effect of GK phosphorylation on GKRP recognition. These studies will provide vital insight into critical components of glucose sensing and mechanisms controlling glucose homeostasis.The broader impact of this research is that it will provide insight into one of the critical components of glucose sensing and the establishment of whole body glucose homeostasis, while enhancing the climate of undergraduate research and the total research infrastructure of both Morehouse College and the consortium of colleges and universities within the Atlanta University Center. In addition, the establishment of this research area will serve as a fundamental component of an endeavor by the Department of Chemistry at Morehouse College to create a Center for Structural Biology for the training of undergraduate students comprised, almost exclusively, of undergraduate African-American men. These and other students from underrepresented groups will be trained in principles of biochemistry and protein X-ray crystallography.