Abstract
Treatment with individual anti-androgens is associated with the development of hot-spot mutations in the androgen receptor (AR). Here, we found that anti-androgens-mt-ARs have similar binary structure to the 5α-dihydrotestosterone-wt-AR. Phage display revealed that these ARs bound to similar peptides, including BUD31, containing an Fxx(F/H/L/W/Y)Y motif cluster with Tyr in the +5 position. Structural analyses of the AR-LBD-BUD31 complex revealed formation of an extra hydrogen bond between the Tyr+5 residue of the peptide and the AR. Functional studies showed that BUD31-related peptides suppressed AR transactivation, interrupted AR N-C interaction, and suppressed AR-mediated cell growth. Combination of peptide screening and X-ray structure analysis may serve as a new strategy for developing anti-ARs that simultaneously suppress both wt and mutated AR function.
Original language | English |
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Pages (from-to) | 1575-1587 |
Number of pages | 13 |
Journal | Molecular Oncology |
Volume | 8 |
Issue number | 8 |
DOIs | |
Publication status | Published - Dec 1 2014 |
Keywords
- Androgen receptor
- Anti-androgen withdrawal syndrome
- BUD31
- Crystallography
- FxxLF
ASJC Scopus subject areas
- Molecular Medicine
- Oncology
- Genetics
- Cancer Research