Abstract
BackgroundThe 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.ResultsMolecular dynamics simulations show that the Y100 side chain can be in "open" or "closed" states with only the former enabling complex formation. When both p53 and MDM2 are in near native conformations, complex formation is rapid and is driven by the formation of a hydrogen bond between W23 of p53 and L54 of MDM2 or by the embedding of F19 of p53 into MDM2. The transition of Y100 from "closed" to "open" can increase the size of the binding site. Interconversions between these two states can be induced by the N-terminal region of MDM2 or by the conformations of the p53 peptides.ConclusionMolecular dynamics simulations have revealed how the binding of p53 to MDM2 is modulated by the conformational mobility of Y100 which is the gatekeeper residue in MDM2. The mobility of this residue can be modulated by the conformations of p53 and the Nterminal lid region of MDM2.
Highlights
The tumor suppressor protein p53 is regulated by the ubiquitin ligase MDM2 which down-regulates p53
Crystallographic, biophysical and computational studies have traditionally shown that F19, W23 and L26 are the three critical residues of the transactivation domain (TA) of p53 which largely determine the stability of its complex with MDM2 [10,25]
In addition to the hydrophobic interactions between these 3 residues and MDM2, the W23 side chain makes an hydrogen bond (HB) with the backbone of L54 of MDM2, and this is very critical for the stability of the complex [7,26]
Summary
The tumor suppressor protein p53 is regulated by the ubiquitin ligase MDM2 which down-regulates p53. The crystal structure (PDB code 1YCR) [10] and molecular dynamics (MD) simulations of the complex of MDM2 and a 13 residue fragment of the transactivation domain of p53 show that Y100 points away from the binding pocket and forms a hydrogen bond (HB) with either the backbones of E28 or N29 of wild type (WT) p53 peptide. This stabilizes an unstructured C-terminal region of the peptide that lies outside the binding pocket [7]. The flip of the latter towards the binding pocket organizes a cozier fit of the ligand and stabilizes an HB with the L26 backbone, suggesting an induced fit mechanism of peptide binding [7]
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