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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-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.

Pubmed ID: 10949035

Authors

  • Rath VL
  • Ammirati M
  • LeMotte PK
  • Fennell KF
  • Mansour MN
  • Danley DE
  • Hynes TR
  • Schulte GK
  • Wasilko DJ
  • Pandit J

Journal

Molecular cell

Publication Data

July 31, 2000

Associated Grants

None

Mesh Terms

  • Adenosine Monophosphate
  • Animals
  • Binding Sites
  • Catalytic Domain
  • Crystallography, X-Ray
  • Diabetes Mellitus
  • Drug Design
  • Enzyme Activation
  • Enzyme Inhibitors
  • Humans
  • In Vitro Techniques
  • Liver
  • Models, Molecular
  • Muscles
  • Phosphorylases
  • Protein Conformation
  • Protein Structure, Secondary
  • Rabbits