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Yeast As a Chassis for Developing Functional Assays to Study Human P53
14:57

Yeast As a Chassis for Developing Functional Assays to Study Human P53

Published on: August 4, 2019

Target structure-based discovery of small molecules that block human p53 and CREB binding protein association

Sachchidanand1, Lois Resnick-Silverman, Sherry Yan

  • 1Structural Biology Program, Department of Physiology and Biophysics, Mount Sinai School of Medicine, New York University, New York 10029, USA.

Chemistry & Biology
|January 24, 2006
PubMed

Insights

Small molecules were developed to block the interaction between acetylated p53 (lysine 382) and the CBP bromodomain. This inhibition is crucial for p53

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Drug Discovery

Background:

  • Lysine acetylation of tumor suppressor p53 is vital for its role in regulating cellular responses to stress, including cell cycle arrest, senescence, and apoptosis.
  • The interaction between acetylated p53 and the CBP bromodomain is essential for p53-mediated transcription of genes like p21, a cell cycle inhibitor.

Purpose of the Study:

  • To discover small molecules that inhibit the association between lysine 382-acetylated p53 and the CBP bromodomain.
  • To characterize the mechanism of inhibition and evaluate the compounds' effects on p53 function in cellular stress response.

Main Methods:

  • Structure-guided screening using nuclear magnetic resonance (NMR) spectroscopy on a focused chemical library.
  • Design of small molecules based on the structural knowledge of the CBP bromodomain/p53-AcK382 complex.
  • Structural characterization of small molecule binding to the CBP bromodomain.
  • Cell-based functional assays to assess the impact on p53 stability and function.

Main Results:

  • Identification of small molecules that effectively block the p53-CBP bromodomain interaction.
  • Structural studies confirmed that these molecules bind to the acetyl-lysine binding site of the CBP bromodomain.
  • Cellular assays demonstrated that the lead compounds can modulate p53 stability and its transcriptional activity in response to DNA damage.

Conclusions:

  • Small molecules targeting the p53-CBP bromodomain interaction offer a novel strategy for modulating p53 function.
  • These inhibitors represent potential therapeutic agents for diseases involving p53 dysregulation, particularly in cancer.
  • The findings provide a structural basis for the rational design of future p53-CBP interaction modulators.

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