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

<div class='caption-title'>MQ bound to C182 in R273H and R273C mutants.</div>
<div class='caption-title'>MQ bound to C229 in R273H and R273C mutants.</div>
<div class='caption-title'>MQ bound to C275 in R273H and R273C mutants.</div>
Degtjarik O, Golovenko D, Diskin-Posner Y, Abrahmsén L, Rozenberg H, Shakked Z
OpenAccess logo Nat Commun 12 7057 (2021)
Related entries: 6znc, 7b46, 7b47, 7b48, 7b4a, 7b4b, 7b4c, 7b4d, 7b4e, 7b4f, 7b4g, 7b4h, 7b4n

Cited: 27 times
EuropePMC logo PMID: 34862374

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.

Reviews citing this publication (13)

  1. Drugging p53 in cancer: one protein, many targets. Hassin O, Oren M. Nat Rev Drug Discov 22 127-144 (2023)
  2. Targeting p53 pathways: mechanisms, structures, and advances in therapy. Wang H, Guo M, Wei H, Chen Y. Signal Transduct Target Ther 8 92 (2023)
  3. Pharmacological reactivation of p53 in the era of precision anticancer medicine. Tuval A, Strandgren C, Heldin A, Palomar-Siles M, Wiman KG. Nat Rev Clin Oncol 21 106-120 (2024)
  4. Targeting Mutant p53 for Cancer Treatment: Moving Closer to Clinical Use? Duffy MJ, Tang M, Rajaram S, O'Grady S, Crown J. Cancers (Basel) 14 4499 (2022)
  5. Gain of Function (GOF) Mutant p53 in Cancer-Current Therapeutic Approaches. Roszkowska KA, Piecuch A, Sady M, Gajewski Z, Flis S. Int J Mol Sci 23 13287 (2022)
  6. Translating p53-based therapies for cancer into the clinic. Peuget S, Zhou X, Selivanova G. Nat Rev Cancer 24 192-215 (2024)
  7. Therapeutic Strategies to Activate p53. Aguilar A, Wang S. Pharmaceuticals (Basel) 16 24 (2022)
  8. Small-molecule correctors and stabilizers to target p53. Fallatah MMJ, Law FV, Chow WA, Kaiser P. Trends Pharmacol Sci 44 274-289 (2023)
  9. Anticancer Therapeutic Strategies Targeting p53 Aggregation. Ferretti GDS, Quarti J, Dos Santos G, Rangel LP, Silva JL. Int J Mol Sci 23 11023 (2022)
  10. Molecular Targeting of the Most Functionally Complex Gene in Precision Oncology: p53. Brown DW, Beatty PH, Lewis JD. Cancers (Basel) 14 5176 (2022)
  11. Refining AML Treatment: The Role of Genetics in Response and Resistance Evaluation to New Agents. Halik A, Arends CM, Bullinger L, Damm F, Frick M. Cancers (Basel) 14 1689 (2022)
  12. Targeting the Molecular and Immunologic Features of Leiomyosarcoma. Cope BM, Traweek RS, Lazcano R, Keung EZ, Lazar AJ, Roland CL, Nassif EF. Cancers (Basel) 15 2099 (2023)
  13. Mediating and maintaining methylation while minimizing mutation: Recent advances on mammalian DNA methyltransferases. Cheng X, Blumenthal RM. Curr Opin Struct Biol 75 102433 (2022)

Articles citing this publication (14)



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