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

本研究项目涉及对维持稳定血糖水平至关重要的两种蛋白质的研究，即葡萄糖激酶(GK)及其调节蛋白葡萄糖激酶调节蛋白(GKRP)。生化分析和X射线结晶学将被用来描述变构在GKRP负调控GK中的结构基础。本项目的具体目标是：(1)确定在果糖-1-磷酸和果糖-6-磷酸存在下大鼠肝脏GKRP的三维结构，(2)使用结晶学数据来模拟形成GK/GKRP复合体所需的相互作用和结构特征，以及(3)评估GK磷酸化对GKRP识别的影响。这些研究将对血糖感知的关键组成部分和控制葡萄糖稳态的机制提供重要的洞察。这项研究的更广泛的影响是，它将提供对血糖感知的关键组成部分之一的洞察和全身葡萄糖稳态的建立，同时增强本科生研究的氛围和亚特兰大大学中心内的莫尔豪斯学院和学院和大学联盟的整体研究基础设施。此外，这一研究领域的建立将是莫尔豪斯学院化学系努力创建一个结构生物学中心的基本组成部分，该中心旨在培训几乎全部由本科生非裔美国人组成的本科生。这些学生和其他来自代表性不足群体的学生将接受生物化学和蛋白质X射线结晶学原理的培训。

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.