title: 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.
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.
authors.affiliation: The George Whipple Lab for Cancer Research, Department of Pathology and Urology, University of Rochester Medical Center, Rochester, NY 14642, USA; Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan 333, Taiwan.
authors.forename: Cheng-Lung
authors.initials: CL
authors.lastname: Hsu
authors.affiliation: Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan 333, Taiwan; Department of Physics, Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu 300, Taiwan.
authors.forename: Jai-Shin
authors.initials: JS
authors.lastname: Liu
authors.affiliation: National Synchrotron Radiation Center, Hsinchu 300, Taiwan.
authors.forename: Po-Long
authors.initials: PL
authors.lastname: Wu
authors.affiliation: National Synchrotron Radiation Center, Hsinchu 300, Taiwan; Department of Physics, Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu 300, Taiwan.
authors.forename: Hong-Hsiang
authors.initials: HH
authors.lastname: Guan
authors.affiliation: The George Whipple Lab for Cancer Research, Department of Pathology and Urology, University of Rochester Medical Center, Rochester, NY 14642, USA; Institute of Oral Medicine, National Cheng Kung University, Tainan 701, Taiwan.
authors.forename: Yuh-Ling
authors.initials: YL
authors.lastname: Chen
authors.affiliation: Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan 333, Taiwan.
authors.forename: An-Chi
authors.initials: AC
authors.lastname: Lin
authors.affiliation: The George Whipple Lab for Cancer Research, Department of Pathology and Urology, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Huei-Ju
authors.initials: HJ
authors.lastname: Ting
authors.affiliation: Division of Urology, Department of Surgery, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan 333, Taiwan.
authors.forename: See-Tong
authors.initials: ST
authors.lastname: Pang
authors.affiliation: The George Whipple Lab for Cancer Research, Department of Pathology and Urology, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Shauh-Der
authors.initials: SD
authors.lastname: Yeh
authors.affiliation: The George Whipple Lab for Cancer Research, Department of Pathology and Urology, University of Rochester Medical Center, Rochester, NY 14642, USA; Sex Hormone Research Center, China Medical University/Hospital, Taichung 104, Taiwan.
authors.forename: Wen-Lung
authors.initials: WL
authors.lastname: Ma
authors.affiliation: National Synchrotron Radiation Center, Hsinchu 300, Taiwan; Department of Physics, Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu 300, Taiwan.
authors.forename: Chung-Jung
authors.initials: CJ
authors.lastname: Chen
authors.affiliation: National Synchrotron Radiation Center, Hsinchu 300, Taiwan; Department of Physics, Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu 300, Taiwan. Electronic address: wgwu@life.nthu.edu.tw.
authors.forename: Wen-Guey
authors.initials: WG
authors.lastname: Wu
authors.affiliation: The George Whipple Lab for Cancer Research, Department of Pathology and Urology, University of Rochester Medical Center, Rochester, NY 14642, USA; Sex Hormone Research Center, China Medical University/Hospital, Taichung 104, Taiwan. Electronic address: chang@urmc.rochester.edu.
authors.forename: Chawnshang
authors.initials: C
authors.lastname: Chang
mesh_terms: D049109:Cell Proliferation / Q000187:drug effects; D047369:Chromatin Immunoprecipitation; D018360:Crystallography, X-Ray; D006801:Humans; D047468:Immunoprecipitation; D008297:Male; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000378:metabolism*; D011485:Protein Binding; D011944:Receptors, Androgen / Q000378:metabolism*; D020349:Surface Plasmon Resonance
chemical_list: C410798:AR protein, human; D010455:Peptides; D011944:Receptors, Androgen
keywords: Androgen receptor; Anti-androgen withdrawal syndrome; BUD31; Crystallography; FxxLF
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