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Quantitative lid dynamics of MDM2 reveals differential ligand binding modes of the p53-binding cleft

Scott A Showalter1, Lei Bruschweiler-Li, Eric Johnson

  • 1Department of Chemistry and Biochemistry, National High Magnetic Field Laboratory, Florida State University, Tallahassee, Florida 32306, USA.

Journal of the American Chemical Society
|April 26, 2008
PubMed

Insights

The MDM2 oncoprotein

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Structural Biology

Background:

  • The MDM2 oncoprotein interacts with the p53 tumor suppressor, regulating its activity and stability.
  • The N-terminal lid of MDM2 is crucial for p53 regulation but its role in ligand binding is poorly understood due to its flexibility.

Purpose of the Study:

  • To investigate the dynamics of the MDM2 N-terminal lid in the presence and absence of ligands.
  • To determine how MDM2 lid dynamics differentiate between p53 binding and small molecule antagonist binding.

Main Methods:

  • Quantitative dynamics study using Nuclear Magnetic Resonance (NMR) spectroscopy.
  • Analysis of apo-MDM2 and MDM2 bound to p53 or the small molecule antagonist nutlin-3.

Main Results:

  • Apo-MDM2 predominantly exists in a closed lid state, which interconverts to a flexible open state upon p53 binding.
  • The small molecule nutlin-3 binds to the MDM2 cleft without significantly altering the closed lid state.
  • MDM2 lid dynamics serve as a distinguishing signature for different ligand interactions.

Conclusions:

  • MDM2 lid dynamics are critical for distinguishing between p53 binding and small molecule antagonist binding.
  • Lid dynamics can be utilized as a screening signature for developing novel therapeutic antagonists targeting the p53-MDM2 interaction.

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