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Simulations of mutant p53 DNA binding domains reveal a novel druggable pocket

Mohan R Pradhan1,2, Jia Wei Siau3, Srinivasaraghavan Kannan1

  • 1Bioinformatics Institute, A*STAR (Agency for Science, Technology and Research), 30 Biopolis Street, #07-01 Matrix, Singapore 138671.

Nucleic Acids Research
|January 17, 2019
PubMed

Insights

Mutations in the p53 DNA binding domain (DBD) can cause unfolding and aggregation. Researchers used simulations to find a new druggable pocket in the p53 DBD, offering potential therapeutic targets.

Area of Science:

  • Biochemistry
  • Structural Biology
  • Computational Biology

Background:

  • The p53 tumor suppressor's DNA binding domain (DBD) is frequently mutated in cancer.
  • Certain mutations destabilize the DBD, leading to unfolding, aggregation, and associated pathologies.

Purpose of the Study:

  • To investigate the dynamics of wild-type (WT) and mutant p53 DBDs using molecular dynamics (MD) simulations.
  • To identify structural changes that initiate DBD unfolding and explore potential therapeutic inhibition strategies.

Main Methods:

  • Extensive all-atom explicit solvent molecular dynamics (MD) simulations.
  • Computational screening of FDA-approved drugs against identified pockets.

Main Results:

  • MD simulations revealed differential conformational sampling in the S6-S7 turn region between WT and mutant p53 DBDs.
  • A novel, druggable pocket was identified in the destabilized mutant DBDs.
  • Computational screening identified potential drug candidates for this pocket.

Conclusions:

  • Mutations in the p53 DBD can trigger unfolding via destabilization of a contiguous turn region.
  • The identified druggable pocket presents a promising target for developing inhibitors against oncogenic p53 mutants.

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