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Yeast As a Chassis for Developing Functional Assays to Study Human P53
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Structural basis of reactivation of oncogenic p53 mutants by a small molecule: methylene quinuclidinone (MQ)

Oksana Degtjarik1, Dmitrij Golovenko1,2, Yael Diskin-Posner3

  • 1Department of Chemical and Structural Biology, Weizmann Institute of Science, 76100, Rehovot, Israel.

Nature Communications
|December 4, 2021
PubMed

Insights

The small molecule methylene quinuclidinone (MQ) reactivates mutant p53 by binding to cysteine residues. Structural studies reveal diverse MQ binding modes that stabilize p53 and restore its function in cancer prevention.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Structural Biology

Background:

  • The tumor suppressor p53 is crucial for cancer prevention, regulating genes in response to genotoxic stress.
  • Mutations in the p53 gene are linked to cancer development.
  • Small molecules like PRIMA-1 and eprenetapopt are converted to methylene quinuclidinone (MQ), which reactivates mutant p53.

Purpose of the Study:

  • To elucidate the structural basis of mutant p53 reactivation by MQ.
  • To understand how MQ interacts with p53 core domains and DNA response elements.

Main Methods:

  • High-resolution crystal structures of p53 core domains (wild-type and cancer-related mutants) were determined.
  • Structures were analyzed in the presence of MQ, both in free state and complexed with DNA response elements.

Main Results:

  • MQ binds to several surface cysteine residues on the p53 core domain.
  • Diverse MQ interaction modes were observed, stabilizing p53 and its DNA complexes.
  • These interactions lead to a common global effect restoring non-functional p53 proteins.

Conclusions:

  • MQ's covalent binding to cysteine residues underlies mutant p53 reactivation.
  • Structural insights reveal how MQ stabilizes p53 and restores its tumor suppressor function.
  • This work provides a foundation for developing p53-targeting cancer therapies.

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