Binding of p53-derived Ligands to MDM2 Induces a Variety of Long Range Conformational Changes

Oliver Schon, Assaf Friedler, Stefan Freund, Alan R. Fersht*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

52 Scopus citations

Abstract

We have used NMR to study the effects of peptide binding on the N-terminal p53-binding domain of human MDM2 (residues 25-109). There were changes in HSQC-chemical shifts throughout the domain on binding four different p53-derived peptide ligands that were significantly large to be indicative of global conformational changes. Large changes in chemical shift were observed in two main regions: the peptide-binding cleft that directly binds the p53 ligands; and the hinge regions connecting the β-sheet and α-helical structures that form the binding cleft. These conformational changes reflect the adaptation of the cleft on binding peptide ligands that differ in length and amino acid composition. Different ligands may induce different conformational transitions in MDM2 that could be responsible for its function. The dynamic nature of MDM2 might be important in the design of anti-cancer drugs that are targeted to its p53-binding site.

Original languageAmerican English
Pages (from-to)197-202
Number of pages6
JournalJournal of Molecular Biology
Volume336
Issue number1
DOIs
StatePublished - 6 Feb 2004
Externally publishedYes

Bibliographical note

Funding Information:
O.S. was supported by a student fellowship from the Friedrich-Ebert-Foundation (GER) and the Medical Research Council (UK). A.F. was supported by a long-term fellowship no. LT00056/2000-M from the Human Frontier Science Program Organisation. The work was also partly supported by the Cancer Research, UK. We thank Dr Mark Bycroft for helpful discussions and suggestions.

Keywords

  • Cancer
  • MDM2
  • NMR
  • Peptide
  • p53

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