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Structure of human MDM2 complexed with RPL11 reveals the molecular basis of p53 activation

Jiangge Zheng1, Yue Lang2, Qi Zhang1

  • 1State Key Laboratory of Agrobiotechnology, China Agricultural University, Beijing 100193, China;

Genes & Development
|July 30, 2015
PubMed

Insights

The MDM2-RPL11 complex structure reveals how ribosomal protein L11 (RPL11) inactivates MDM2, activating tumor suppressor p53. This discovery offers a structural basis for developing new anti-cancer drugs targeting this interaction.

Area of Science:

  • Molecular Biology
  • Structural Biology
  • Cancer Research

Background:

  • The central region of MDM2 is crucial for p53 activation and tumor suppression.
  • Ribosomal stress triggers binding of ribosomal protein L11 (RPL11) to MDM2, leading to MDM2 inactivation and p53 activation.

Purpose of the Study:

  • To elucidate the structural basis of the MDM2-RPL11 interaction.
  • To understand the mechanism of p53 activation via MDM2-RPL11 complex formation.

Main Methods:

  • X-ray crystallography to determine the structure of the human MDM2-RPL11 complex at 2.4 Å resolution.
  • Cellular assays to assess the impact of RPL11 binding on p53 activation in the presence of MDM2 mutants.

Main Results:

  • The crystal structure reveals extensive interactions between MDM2 and RPL11, involving MDM2's acidic domain and zinc fingers.
  • Complex formation induces significant conformational changes in both MDM2 and RPL11.
  • RPL11's inability to bind MDM2 mutants prevents p53 activation in cellular models.
  • MDM2's C4 zinc finger is critical for RPL11 binding, mimicking 28S rRNA interactions.

Conclusions:

  • The RPL11-MDM2 interaction is essential for p53 activation and tumor suppression.
  • The determined structure provides a foundation for designing novel anti-cancer therapeutics targeting this pathway.
Keywords:
RPL11—MDM2cancercomplex structuremolecular basisp53 activation

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