Identification of a new androgen receptor (AR) co-regulator BUD31 and related peptides to suppress wild-type and mutated AR-mediated prostate cancer growth via peptide screening and X-ray structure analysis
| Autor: | An Chi Lin, Shauh Der Yeh, Wen Lung Ma, Cheng Lung Hsu, Chung Jung Chen, Chawnshang Chang, Huei Ju Ting, Wen-guey Wu, Po Long Wu, Yuh Ling Chen, Jai Shin Liu, Hong Hsiang Guan, See Tong Pang |
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| Rok vydání: | 2014 |
| Předmět: |
Male
Chromatin Immunoprecipitation Cancer Research Phage display Immunoprecipitation Peptide Plasma protein binding Biology Crystallography X-Ray Transactivation Genetics Humans Research Articles Cell Proliferation chemistry.chemical_classification Cell growth Wild type Prostatic Neoplasms General Medicine Surface Plasmon Resonance Molecular biology Androgen receptor Oncology chemistry Receptors Androgen Molecular Medicine Peptides Protein Binding |
| Zdroj: | Molecular Oncology. 8:1575-1587 |
| ISSN: | 1574-7891 |
| DOI: | 10.1016/j.molonc.2014.06.009 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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