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

Scott A. Showalter, Lei Bruschweiler-Li, Eric Johnson, Fengli Zhang, Rafael Brüschweiler

Research output: Contribution to journalArticle

65 Citations (Scopus)

Abstract

The oncoprotein MDM2 regulates the activity and stability of the tumor suppressor p53 through protein-protein interaction involving their N-terminal domains. The N-terminal lid of MDM2 has been implicated in p53 regulation; however, due to its flexible nature, limited data are available concerning its role in ligand binding. The quantitative dynamics study using NMR reported here shows, for the first time, that the lid in apo-MDM2 slowly interconverts between a "closed" state that is associated with the p53-binding cleft and an "open" state that is highly flexible. Our results reveal that apo-MDM2 predominantly populates the closed state, whereas the p53-bound MDM2 exclusively populates the open state. Unlike p53 binding, the small molecule MDM2 antagonist nutlin-3 binds to the cleft essentially without perturbing the closed lid state. The lid dynamics thereby represents a signature for the experimental and virtual screening of therapeutic antagonists that target the p53-MDM2 interaction.

Original languageEnglish (US)
Pages (from-to)6472-6478
Number of pages7
JournalJournal of the American Chemical Society
Volume130
Issue number20
DOIs
StatePublished - May 21 2008

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Tumor Suppressor Protein p53
Oncogene Proteins
Ligands
Proteins
Tumors
Screening
Nuclear magnetic resonance
Molecules
Therapeutics
nutlin 3

All Science Journal Classification (ASJC) codes

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

Cite this

Showalter, Scott A. ; Bruschweiler-Li, Lei ; Johnson, Eric ; Zhang, Fengli ; Brüschweiler, Rafael. / Quantitative lid dynamics of MDM2 reveals differential ligand binding modes of the p53-binding cleft. In: Journal of the American Chemical Society. 2008 ; Vol. 130, No. 20. pp. 6472-6478.
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Quantitative lid dynamics of MDM2 reveals differential ligand binding modes of the p53-binding cleft. / Showalter, Scott A.; Bruschweiler-Li, Lei; Johnson, Eric; Zhang, Fengli; Brüschweiler, Rafael.

In: Journal of the American Chemical Society, Vol. 130, No. 20, 21.05.2008, p. 6472-6478.

Research output: Contribution to journalArticle

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