Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
10914873 | Molecular Oncology | 2014 | 13 Pages |
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.
Keywords
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Authors
Cheng-Lung Hsu, Jai-Shin Liu, Po-Long Wu, Hong-Hsiang Guan, Yuh-Ling Chen, An-Chi Lin, Huei-Ju Ting, See-Tong Pang, Shauh-Der Yeh, Wen-Lung Ma, Chung-Jung Chen, Wen-Guey Wu, Chawnshang Chang,