Patrick E. Hanna, Principal Investigator

Design of Proteasome Inhibitor

  The proteasome is a multicatalytic protease complex that is involved in intracellular protein turnover in all three kingdoms of life. The proteasome is located in both the cytosol and the nucleus and acts in the degradation of abnormal, mis- folded, or improperly assembled proteins, in stress response, cell cycle control, cell differentiation, metabolic adaptation, and cellular immune response. It is also involved in many pathophysiological processes, such as inflammation and cancer, and constitutes a promising target for drug design.

  The crystal structure of the 20S proteasome from Saccharomyces cerevisiae revealed an overall assembly of the 28 subunits, which are arranged as a stack of four heptameric rings to form a cylindrical particle. Only three of the seven different subunits of one ring-i.e., 1, 2, and 5-are autoprocessed with the generation of the N-terminal nucleophile, the Thr1 residue essential for activity.

  The main purpose of this project was to design specific inhibitors targeting to Thr1 residue in the active site. Available crystal structure of proteasome makes structure-based rational drug design possible. In order to examine whether the designed compounds bearing conformations are similar to that of the natural substrate to proteasome, one needs a computational method, which is intended to help refine the design.