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Structural basis of reactivation of oncogenic p53 mutants by a small molecule: methylene quinuclidinone (MQ)

Author

Listed:
  • Oksana Degtjarik

    (Weizmann Institute of Science)

  • Dmitrij Golovenko

    (Weizmann Institute of Science
    University of Massachusetts Medical School, RNA Therapeutics Institute)

  • Yael Diskin-Posner

    (Weizmann Institute of Science)

  • Lars Abrahmsén

    (Aprea Therapeutics AB)

  • Haim Rozenberg

    (Weizmann Institute of Science)

  • Zippora Shakked

    (Weizmann Institute of Science)

Abstract

In response to genotoxic stress, the tumor suppressor p53 acts as a transcription factor by regulating the expression of genes critical for cancer prevention. Mutations in the gene encoding p53 are associated with cancer development. PRIMA-1 and eprenetapopt (APR-246/PRIMA-1MET) are small molecules that are converted into the biologically active compound, methylene quinuclidinone (MQ), shown to reactivate mutant p53 by binding covalently to cysteine residues. Here, we investigate the structural basis of mutant p53 reactivation by MQ based on a series of high-resolution crystal structures of cancer-related and wild-type p53 core domains bound to MQ in their free state and in complexes with their DNA response elements. Our data demonstrate that MQ binds to several cysteine residues located at the surface of the core domain. The structures reveal a large diversity in MQ interaction modes that stabilize p53 and its complexes with DNA, leading to a common global effect that is pertinent to the restoration of non-functional p53 proteins.

Suggested Citation

  • Oksana Degtjarik & Dmitrij Golovenko & Yael Diskin-Posner & Lars Abrahmsén & Haim Rozenberg & Zippora Shakked, 2021. "Structural basis of reactivation of oncogenic p53 mutants by a small molecule: methylene quinuclidinone (MQ)," Nature Communications, Nature, vol. 12(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-27142-6
    DOI: 10.1038/s41467-021-27142-6
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    References listed on IDEAS

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    1. Christopher D. Wassman & Roberta Baronio & Özlem Demir & Brad D. Wallentine & Chiung-Kuang Chen & Linda V. Hall & Faezeh Salehi & Da-Wei Lin & Benjamin P. Chung & G. Wesley Hatfield & A. Richard Chamb, 2013. "Computational identification of a transiently open L1/S3 pocket for reactivation of mutant p53," Nature Communications, Nature, vol. 4(1), pages 1-9, June.
    2. David S. Liu & Cuong P. Duong & Sue Haupt & Karen G. Montgomery & Colin M. House & Walid J. Azar & Helen B. Pearson & Oliver M. Fisher & Matthew Read & Glen R. Guerra & Ygal Haupt & Carleen Cullinane , 2017. "Inhibiting the system xC−/glutathione axis selectively targets cancers with mutant-p53 accumulation," Nature Communications, Nature, vol. 8(1), pages 1-14, April.
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