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

Area of Science:

• Biochemistry
• Molecular Biology
• Structural Biology

Background:

• The tumor suppressor protein p53 is negatively regulated by the ubiquitin ligase MDM2.
• In cancer, overexpressed MDM2 can be targeted to stabilize p53, offering a therapeutic strategy.
• p53's interaction with MDM2 involves hydrophobic residues (F19, W23, L26) binding to MDM2's plastic ligand pocket, influenced by Y100.

Purpose of the Study:

• To investigate the role of Y100 residue dynamics in the recognition and binding of p53 by MDM2.
• To understand how Y100's conformational mobility influences the p53-MDM2 interaction.

Main Methods:

• Utilized molecular dynamics simulations to study the conformational states of Y100.
• Analyzed the impact of Y100's "open" and "closed" states on complex formation.
• Investigated factors inducing transitions between Y100 states.

Main Results:

• Y100 exists in "open" and "closed" states; only the "open" state permits p53-MDM2 complex formation.
• Complex formation is rapid when p53 and MDM2 are near native conformations, driven by specific residue interactions (e.g., p53 W23-MDM2 L54 hydrogen bond).
• The "open" state of Y100 increases the binding site size, and transitions are influenced by MDM2's N-terminal region and p53 peptide conformations.

Conclusions:

• MDM2's Y100 residue acts as a gatekeeper, modulating p53 binding through its conformational mobility.
• The dynamics of Y100 are crucial for regulating the p53-MDM2 interaction.
• p53 conformation and MDM2's N-terminal lid region can influence Y100 mobility, offering insights into therapeutic targeting.