Human liver glycogen phosphorylase inhibitors bind at a new allosteric site

Background: Glycogen phosphorylases catalyze the breakdown of glycogen to g lucose-l-phosphate for glycolysis. Maintaining control of blood glucose lev els is critical in minimizing the debilitating effects of diabetes, making liver glycogen phosphorylase a potential therapeutic target. Results: The binding site in human liver glycogen phosphorylase (HLGP) for a class of promising antidiabetic agents was identified crystallographicall y. The site is novel and functions allosterically by stabilizing the inacti ve conformation of HLGP. The initial view of the complex revealed key struc tural information and inspired the design of a new class of inhibitors whic h bind with nanomolar affinity and whose crystal structure is also describe d. Conclusions: We have identified the binding site of a new class of alloster ic HLGP inhibitors. The crystal structure revealed the details of inhibitor binding, led to the design of a new class of compounds, and should acceler ate efforts to develop therapeutically relevant molecules for the treatment of diabetes.