Human liver glycogen phosphorylase inhibitors bind at a new allosteric site
| Autor: | R. Kirk McPherson, E. Michael Gibbs, Judith L. Treadway, Alan M. Mathiowetz, Jennifer L Ekstrom, Mark Ammirati, Thanh V. Olson, Dennis E. Danley, Dennis J. Hoover, Virginia L. Rath, Thomas R Hynes |
|---|---|
| Rok vydání: | 2000 |
| Předmět: |
Models
Molecular Indoles Phosphorylases Protein Conformation Allosteric regulation Clinical Biochemistry Biology Crystallography X-Ray Biochemistry Drug design Protein Structure Secondary X-ray chemistry.chemical_compound Glycogen phosphorylase Drug Discovery Humans Hypoglycemic Agents Glycolysis Phosphorylation Binding site Enzyme Inhibitors Phosphorylase kinase Glycogen synthase Molecular Biology Pharmacology Binding Sites Glycogen Crystal structure Incidence Diabetes General Medicine United States chemistry Diabetes Mellitus Type 2 Liver biology.protein Molecular Medicine Allosteric Site |
| Zdroj: | Chemistrybiology. 7(9) |
| ISSN: | 1074-5521 |
| Popis: | Background : Glycogen phosphorylases catalyze the breakdown of glycogen to glucose-1-phosphate for glycolysis. Maintaining control of blood glucose levels 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 crystallographically. The site is novel and functions allosterically by stabilizing the inactive conformation of HLGP. The initial view of the complex revealed key structural information and inspired the design of a new class of inhibitors which bind with nanomolar affinity and whose crystal structure is also described. Conclusions : We have identified the binding site of a new class of allosteric HLGP inhibitors. The crystal structure revealed the details of inhibitor binding, led to the design of a new class of compounds, and should accelerate efforts to develop therapeutically relevant molecules for the treatment of diabetes. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|