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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

Structural basis for understanding oncogenic p53 mutations and designing rescue drugs

Andreas C Joerger1, Hwee Ching Ang, Alan R Fersht

  • 1Cambridge University Chemical Laboratory and Cambridge Centre for Protein Engineering, Medical Research Council Centre, Hills Road, Cambridge CB2 2QH, United Kingdom.

Proceedings of the National Academy of Sciences of the United States of America
|October 4, 2006
PubMed

Insights

Mutations in the tumor suppressor p53 protein, common in cancer, disrupt its DNA binding. Crystal structures reveal how these mutations inactivate p53, offering targets for potential drug therapies.

Area of Science:

  • Structural Biology
  • Cancer Biology
  • Drug Discovery

Background:

  • The tumor suppressor protein p53 plays a crucial role in preventing cancer.
  • Mutations in the DNA-binding domain of p53 are found in about 50% of human cancers, leading to its inactivation.

Purpose of the Study:

  • To elucidate the structural basis of oncogenic p53 mutations.
  • To provide insights for developing drugs that could restore the function of inactivated p53 mutants.

Main Methods:

  • High-resolution crystal structure determination of several oncogenic p53 mutants.
  • Analysis of structural changes and their impact on DNA binding and protein stability.

Main Results:

  • Mutations cause diverse structural alterations, including loss of DNA contact, formation of cavities, DNA-binding surface distortion, and disruption of tetramerization interfaces.
  • These structural changes correlate with altered functional properties and phenotypes, such as temperature sensitivity.
  • Identified potential drug targets, including generic stabilizing agents and mutant-specific crevice-targeting drugs.

Conclusions:

  • The structural heterogeneity of p53 mutants explains their varied functional consequences.
  • Specific structural features of mutants, like crevices, present opportunities for rational drug design to rescue p53 tumor suppressor activity.

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