Journal
MOLECULAR ONCOLOGY
Volume 8, Issue 8, Pages 1575-1587Publisher
WILEY
DOI: 10.1016/j.molonc.2014.06.009
Keywords
FxxLF; BUD31; Crystallography; Anti-androgen withdrawal syndrome; Androgen receptor
Categories
Funding
- NIH [CA127300]
- George Whipple Professorship Endowment, Taiwan National Science Council [NSC98-2314-B-182A-053-MY3]
- Taiwan Ministry of Health and Welfare Clinical Trial and Research Center of Excellence [DOH102-TD-B-111-004]
- Chang Gung Memorial Hospital [CMRPG-390061, CMRPG-300171, CMRPG-3B0421, CMRPG-3B1261-2, CMRPG-3C0201]
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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 5 alpha-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. (C) 2014 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.
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