PROTEIN GRAFTING--INHIBITION OF P53 MDM2 COMPLEXATION

Yale University, New Haven CT

Investigators

Abstract

Previous work has shown that the transcriptional activation function of the tumor-suppressor p53 is inhibited upon complexation of MDM2, a protein that is over expressed in a large fraction of solid tumors. The three dimensional structure of the complex shows a 15 residue fragment of the p15 residue fragment of the p53 activation domain bound as an alpha-helix in a deep cleft on the MDM2 surface. This proposal applies the recently described technique of protein grafting the design of miniature proteins that bind selectively to MDM2 and inhibit formation of the complex between MDM2 and wt p5. It is our hope that these molecules will increase our general understanding of how to design ligands for protein surfaces as well as provide prototypes for the development of selective MDM2 antagonists.