Rath V L, Ammirati M, LeMotte P K, Fennell K F, Mansour M N, Danley D E, Hynes T R, Schulte G K, Wasilko D J, Pandit J
Exploratory Medicinal Sciences, Global Research and Development, Groton Laboratories, Pfizer, Inc, Connecticut 06340, USA.
Mol Cell. 2000 Jul;6(1):139-48.
Glycogen phosphorylases catalyze the breakdown of glycogen to glucose-1-phosphate, which enters glycolysis to fulfill the energetic requirements of the organism. Maintaining control of blood glucose levels is critical in minimizing the debilitating effects of diabetes, making liver glycogen phosphorylase a potential therapeutic target. To support inhibitor design, we determined the crystal structures of the active and inactive forms of human liver glycogen phosphorylase a. During activation, forty residues of the catalytic site undergo order/disorder transitions, changes in secondary structure, or packing to reorganize the catalytic site for substrate binding and catalysis. Knowing the inactive and active conformations of the liver enzyme and how each differs from its counterpart in muscle phosphorylase provides the basis for designing inhibitors that bind preferentially to the inactive conformation of the liver isozyme.
糖原磷酸化酶催化糖原分解为葡萄糖-1-磷酸，葡萄糖-1-磷酸进入糖酵解以满足机体的能量需求。维持血糖水平的控制对于将糖尿病的衰弱影响降至最低至关重要，这使得肝糖原磷酸化酶成为一个潜在的治疗靶点。为了支持抑制剂设计，我们确定了人肝糖原磷酸化酶a的活性和非活性形式的晶体结构。在激活过程中，催化位点的40个残基经历有序/无序转变、二级结构变化或堆积，以重组催化位点用于底物结合和催化。了解肝酶的非活性和活性构象以及每种构象与肌肉磷酸化酶中的对应构象有何不同，为设计优先结合肝同工酶非活性构象的抑制剂提供了基础。
