Evaluation of ligand-dependent changes in AR structure using peptide probes.

Area of Science:

• Molecular Endocrinology
• Cancer Biology
• Structural Biology

Background:

• Mutations in the androgen receptor (AR) are common in recurrent prostate cancers.
• These mutations can alter AR pharmacology, enabling non-androgenic compounds to activate the receptor.

Purpose of the Study:

• To investigate the molecular mechanisms behind aberrant AR pharmacology in prostate cancer.
• To probe the conformation of the AR's AF-2/coactivator binding pocket in the presence of various ligands and AR mutants.

Main Methods:

• Utilized a series of LxxLL-containing peptides to study AR conformation.
• Examined AR variants found in anti-hormone refractory prostate cancers with different ligands.
• Assessed the impact of AF2-binding peptides on AR amino and carboxyl terminus interactions.

Main Results:

• Identified peptides that bind wild-type AR dependently on agonists.
• Observed these peptides also interact with AR variants in the presence of androgens or antiandrogens.
• Found that AR-AF2 stabilizes receptor structure, facilitating N-terminal coactivator interaction, and peptide overexpression blocks this interaction without reducing transcriptional activity.

Conclusions:

• Aberrant AR pharmacology in prostate cancer arises from mutations enabling an active AF-2 conformation with antagonists or nonclassical ligands.
• AR-AF2's role is crucial for stabilizing receptor structure, indirectly promoting coactivator interaction.
• Overexpression of AF2-binding peptides or AR N-terminus stabilizes agonist binding by decreasing ligand off-rate, contributing to resistance.