Activation of human liver glycogen phosphorylase by alteration of the secondary structure and packing of the catalytic core

Glycogen phosphorylases catalyze the breakdown of glycogen to glucose-1-pho sphate, which enters glycolysis to fulfill the energetic requirements of th e organism. Maintaining control of blood glucose levels is critical in mini mizing the debilitating effects of diabetes, making liver glycogen phosphor ylase a potential therapeutic target. To support inhibitor design, we deter mined the crystal structures of the active and inactive forms of human live r glycogen phosphorylase a. During activation, forty residues of the cataly tic site undergo order/disorder transitions, changes in secondary structure , or packing to reorganize the catalytic site for substrate binding and cat alysis. Knowing the inactive and active conformations of the liver enzyme a nd how each differs from its counterpart in muscle phosphorylase provides t he basis for designing inhibitors that bind preferentially to the inactive conformation of the liver isozyme.