Modulation of p53 binding to MDM2: computational studies reveal important roles of Tyr100.

ABSTRACT:

Background

The tumor suppressor protein p53 is regulated by the ubiquitin ligase MDM2 which down-regulates p53. In tumours with overexpressed MDM2, the p53-MDM2 interaction can be interrupted by a peptide or small molecule to stabilize p53 as a therapeutic strategy. Structural and biochemical/mutagenesis data show that p53 has 3 hydrophobic residues F19, W23 and L26 that embed into the ligand binding pocket of MDM2 which is highly plastic in nature and can modulate its size to accommodate a variety of ligands. This binding pocket is primarily dependent on the orientation of a particular residue, Y100. We have studied the role of the dynamics of Y100 in p53 recognition.

Results

Molecular dynamics simulations show that the Y100 side chain can be in "open" or "closed" states wi

SUBMITTER: Dastidar SG 

PROVIDER: S-EPMC2788357 | biostudies-literature | 2009 Dec

REPOSITORIES: biostudies-literature