Transient protein states in designing inhibitors of the MDM2-p53 interaction

Structure. 2013 Dec 3;21(12):2143-51. doi: 10.1016/j.str.2013.09.006. Epub 2013 Oct 24.


Reactivation of p53 by release of the functional protein from its inhibition by MDM2 provides an efficient, nongenotoxic approach to a wide variety of cancers. We present the cocrystal structures of two complexes of MDM2 with inhibitors based on 6-chloroindole scaffolds. Both molecules bound to a distinct conformational state of MDM2 with nM-μM affinities. In contrast to other structurally characterized antagonists, which mimic three amino acids of p53 (Phe19, Trp23, and Leu26), the compounds induced an additional hydrophobic pocket on the MDM2 surface and unveiled a four-point binding mode. The enlarged interaction interface of the inhibitors resulted in extension of small molecules binding toward the "lid" segment of MDM2 (residues 19-23)--a nascent element that interferes with p53 binding. As supported by protein engineering and molecular dynamics studies, employing these unstable elements of MDM2 provides an efficient and yet unexplored alternative in development of MDM2-p53 association inhibitors.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Crystallography, X-Ray
  • Dipeptides / chemistry*
  • Humans
  • Hydroxamic Acids / chemistry*
  • Molecular Dynamics Simulation
  • Molecular Structure
  • Nuclear Magnetic Resonance, Biomolecular
  • Protein Interaction Domains and Motifs
  • Proto-Oncogene Proteins c-mdm2 / antagonists & inhibitors
  • Proto-Oncogene Proteins c-mdm2 / chemistry*
  • Tryptophan / analogs & derivatives*
  • Tryptophan / chemistry
  • Tumor Suppressor Protein p53 / antagonists & inhibitors
  • Tumor Suppressor Protein p53 / chemistry*


  • Dipeptides
  • Hydroxamic Acids
  • KK271 compound
  • Tumor Suppressor Protein p53
  • YH300 compound
  • Tryptophan
  • MDM2 protein, human
  • Proto-Oncogene Proteins c-mdm2

Associated data

  • PDB/4MDN
  • PDB/4MDQ