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Structural studies of p53 inactivation by DNA-contact mutations and its rescue by suppressor mutations via alternative protein-DNA interactions.

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Eldar A, Rozenberg H, Diskin-Posner Y, Rohs R, Shakked Z
OpenAccess logo Nucleic Acids Res 41 8748-59 (2013)
Related entries: 4ibq, 4ibs, 4ibt, 4ibu, 4ibv, 4iby, 4ibz, 4ijt

Cited: 42 times
EuropePMC logo PMID: 23863845

Abstract

A p53 hot-spot mutation found frequently in human cancer is the replacement of R273 by histidine or cysteine residues resulting in p53 loss of function as a tumor suppressor. These mutants can be reactivated by the incorporation of second-site suppressor mutations. Here, we present high-resolution crystal structures of the p53 core domains of the cancer-related proteins, the rescued proteins and their complexes with DNA. The structures show that inactivation of p53 results from the incapacity of the mutated residues to form stabilizing interactions with the DNA backbone, and that reactivation is achieved through alternative interactions formed by the suppressor mutations. Detailed structural and computational analysis demonstrates that the rescued p53 complexes are not fully restored in terms of DNA structure and its interface with p53. Contrary to our previously studied wild-type (wt) p53-DNA complexes showing non-canonical Hoogsteen A/T base pairs of the DNA helix that lead to local minor-groove narrowing and enhanced electrostatic interactions with p53, the current structures display Watson-Crick base pairs associated with direct or water-mediated hydrogen bonds with p53 at the minor groove. These findings highlight the pivotal role played by R273 residues in supporting the unique geometry of the DNA target and its sequence-specific complex with p53.

Reviews - 4ibw mentioned but not cited (1)

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Reviews citing this publication (8)

  1. The p53 Pathway: Origins, Inactivation in Cancer, and Emerging Therapeutic Approaches. Joerger AC, Fersht AR. Annu Rev Biochem 85 375-404 (2016)
  2. Molecular Mechanisms of p53 Deregulation in Cancer: An Overview in Multiple Myeloma. Herrero AB, Rojas EA, Misiewicz-Krzeminska I, Krzeminski P, Gutiérrez NC. Int J Mol Sci 17 E2003 (2016)
  3. Structural and sequential context of p53: A review of experimental and theoretical evidence. Saha T, Kar RK, Sa G. Prog Biophys Mol Biol 117 250-263 (2015)
  4. Structural and Drug Targeting Insights on Mutant p53. Gomes AS, Ramos H, Inga A, Sousa E, Saraiva L. Cancers (Basel) 13 3344 (2021)
  5. Medicinal Effect, In Silico Bioactivity Prediction, and Pharmaceutical Formulation of Ageratum conyzoides L.: A Review. Kotta JC, Lestari ABS, Candrasari DS, Hariono M. Scientifica (Cairo) 2020 6420909 (2020)
  6. Targeting p53 pathways: mechanisms, structures, and advances in therapy. Wang H, Guo M, Wei H, Chen Y. Signal Transduct Target Ther 8 92 (2023)
  7. Small-molecule correctors and stabilizers to target p53. Fallatah MMJ, Law FV, Chow WA, Kaiser P. Trends Pharmacol Sci 44 274-289 (2023)
  8. Challenges and Prospects of Patient-Derived Xenografts for Cancer Research. Jin J, Yoshimura K, Sewastjanow-Silva M, Song S, Ajani JA. Cancers (Basel) 15 4352 (2023)

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