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Full-length p53 tetramer bound to DNA and its quaternary dynamics

Ö Demir1, P U Ieong1,2, R E Amaro1,2

  • 1Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA, USA.

Oncogene
|September 20, 2016
PubMed

Insights

Researchers modeled the full-length p53 (fl-p53) tetramer

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Structural Biology

Background:

  • The tumor suppressor p53 is frequently inactivated in human cancers, making its reactivation a key therapeutic goal.
  • Structural characterization of full-length p53 (fl-p53) is difficult due to its complex, flexible nature.

Purpose of the Study:

  • To explore the structural dynamics and DNA-binding modes of the full-length p53 (fl-p53) tetramer.
  • To identify potential druggable pockets for future anticancer drug discovery.

Main Methods:

  • Developed atomistic integrative models of fl-p53 tetramers bound to three distinct DNA sequences.
  • Performed extensive all-atom molecular dynamics simulations (nearly 1 μs total).
  • Utilized collective principal component analysis and solvent mapping.

Main Results:

  • Generated stable models consistent with electron microscopy data.
  • Revealed direct interactions between the p53 C-terminus and DNA for the first time.
  • Identified sequence-dependent variations in p53 tetramer binding and L1 loop dynamics.
  • Discovered potential druggable pockets on the fl-p53 structure.

Conclusions:

  • This study provides unprecedented insights into fl-p53 structural dynamics and DNA interactions.
  • The identified druggable pockets offer promising avenues for developing novel p53-reactivating anticancer therapies.

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