Systematic mutational analysis of peptide inhibition of the p53-MDM2/MDMX interactions.

ABSTRACT: Inhibition of the interaction between the tumor suppressor protein p53 and its negative regulators MDM2 and MDMX is of great interest in cancer biology and drug design. We previously reported a potent duodecimal peptide inhibitor, termed PMI (TSFAEYWNLLSP), of the p53-MDM2 and -MDMX interactions. PMI competes with p53 for MDM2 and MDMX binding at an affinity roughly 2 orders of magnitude higher than that of (17-28)p53 (ETFSDLWKLLPE) of the same length; both peptides adopt nearly identical alpha-helical conformations in the complexes, where the three highlighted hydrophobic residues Phe, Trp, and Leu dominate PMI or (17-28)p53 binding to MDM2 and MDMX. To elucidate the molecular determinants for PMI activity and specificity, we performed a systematic Ala scanning mutational analysis of PMI

SUBMITTER: Li C 

PROVIDER: S-EPMC2856455 | biostudies-literature | 2010 Apr

REPOSITORIES: biostudies-literature