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A hotspot for posttranslational modifications on the androgen receptor dimer interface drives pathology and

Andrea Alegre-Martí1,2, Alba Jiménez-Panizo1,2, Adrián Martínez-Tébar3

  • 1Structural Biology of Nuclear Receptors, Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, University of Barcelona (UB), 08028 Barcelona, Spain.

Science Advances
|March 15, 2023
PubMed

Insights

Prostate cancer mutations in the androgen receptor (AR) alter its function. A newly found allosteric switch in the AR ligand-binding domain (AR-LBD) affects transcription and anti-androgen response, offering new precision medicine avenues.

Area of Science:

  • Molecular biology
  • Structural biology
  • Genetics

Background:

  • Androgen receptor (AR) mutations are linked to prostate cancer and androgen insensitivity syndrome.
  • Existing structural data do not fully explain how mutations impact AR function.
  • Understanding AR structure-function relationships is crucial for targeted therapies.

Purpose of the Study:

  • To investigate the structural and functional consequences of AR mutations at the ligand-binding domain dimer interface.
  • To elucidate the mechanism by which these mutations affect AR-dependent transcription and drug response.

Main Methods:

  • X-ray crystallography
  • In vitro biochemical assays
  • In silico modeling
  • Cell-based functional assays

Main Results:

  • Selected AR mutations alter AR-dependent transcription and response to anti-androgens.
  • These variants induce a novel allosteric switch in the AR ligand-binding domain (AR-LBD).
  • The allosteric switch increases exposure of Arg761, a key methylation site, and highlights the roles of Arg761 and Tyr764 in AR dimerization and function.

Conclusions:

  • Allosteric coupling between AR dimerization and post-translational modifications represents a disease mechanism.
  • Findings have implications for developing precision medicine strategies for prostate cancer.
  • Targeting AR allosteric regulation could offer new therapeutic approaches.

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