title: The environmental endocrine disruptor p-nitrophenol interacts with FKBP51, a positive regulator of androgen receptor and inhibits androgen receptor signaling in human cells.
abstract: The compound p-nitrophenol, which shows the anti-androgenic activity, can easily become anthropogenic pollutants and pose a threat to the environment and human health. Previous work indicates that the anti-androgenic mechanism of p-nitrophenol is complex and may involve several components in the AR signaling pathway, but the molecular details of how p-nitrophenol inhibits AR signaling are still not quite clear. Here, we characterized p-nitrophenol binds to the FK1 domain of an AR positive regulator FKBP51 with micromolar affinity and structural analysis of FK1 domain in complex with p-nitrophenol revealed that p-nitrophenol occupies a hydrophobic FK1 pocket that is vital for AR activity enhancement. Molecular dynamics simulation indicated that p-nitrophenol is stably bound to the FK1 pocket and the hotspot residues that involved p-nitrophenol binding are mainly hydrophobic and overlap with the AR interaction site. Furthermore, we showed that p-nitrophenol inhibits the androgen-dependent growth of human prostate cancer cells, possibly through down-regulating the expression levels of AR activated downstream genes. Taken together, our data suggests that p-nitrophenol suppresses the AR signaling pathway at least in part by blocking the interaction between AR and its positive regulator FKBP51. We believe that our findings could provide new guidelines for assessing the potential health effects of p-nitrophenol.
authors.affiliation: School of Life Sciences, Lanzhou University, Lanzhou 730000, PR China; Institute of Urology, Lanzhou University Second Hospital, Key Laboratory of Urological Diseases in Gansu Province, Gansu Nephro-Urological Clinical Center, Lanzhou, Gansu 730000, PR China.
authors.forename: Dan
authors.initials: D
authors.lastname: Wu
authors.affiliation: School of Life Sciences, Lanzhou University, Lanzhou 730000, PR China.
authors.forename: Xuanyu
authors.initials: X
authors.lastname: Tao
authors.affiliation: School of Life Sciences, Lanzhou University, Lanzhou 730000, PR China; Cuiying Honors College, Lanzhou University, Lanzhou 730000, PR China.
authors.forename: Zhi-Peng
authors.initials: ZP
authors.lastname: Chen
authors.affiliation: School of Life Sciences, Lanzhou University, Lanzhou 730000, PR China.
authors.forename: Jian-Ting
authors.initials: JT
authors.lastname: Han
authors.affiliation: School of Life Sciences, Lanzhou University, Lanzhou 730000, PR China.
authors.forename: Wen-Juan
authors.initials: WJ
authors.lastname: Jia
authors.affiliation: MOE Key Laboratory of Cell Activities and Stress Adaptations, School of Life Sciences, Lanzhou University, Lanzhou 730000, PR China.
authors.forename: Ning
authors.initials: N
authors.lastname: Zhu
authors.affiliation: School of Life Sciences, Lanzhou University, Lanzhou 730000, PR China.
authors.forename: Xiangkai
authors.initials: X
authors.lastname: Li
authors.affiliation: Institute of Urology, Lanzhou University Second Hospital, Key Laboratory of Urological Diseases in Gansu Province, Gansu Nephro-Urological Clinical Center, Lanzhou, Gansu 730000, PR China. Electronic address: erywzp@lzu.edu.cn.
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Wang
authors.affiliation: School of Life Sciences, Lanzhou University, Lanzhou 730000, PR China; MOE Key Laboratory of Cell Activities and Stress Adaptations, School of Life Sciences, Lanzhou University, Lanzhou 730000, PR China; Gansu Key Laboratory of Biomonitoring and Bioremediation for Environmental Pollution, School of Life Sciences, Lanzhou University, Lanzhou, PR China. Electronic address: heyx@lzu.edu.cn.
authors.forename: Yong-Xing
authors.initials: YX
authors.lastname: He
mesh_terms: D059002:Androgen Receptor Antagonists / Q000737:chemistry / Q000633:toxicity*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D052244:Endocrine Disruptors / Q000737:chemistry / Q000633:toxicity*; D006801:Humans; D056004:Molecular Dynamics Simulation; D009596:Nitrophenols / Q000737:chemistry / Q000633:toxicity*; D017434:Protein Structure, Tertiary; D011944:Receptors, Androgen / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D022021:Tacrolimus Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D000099159:Tacrolimus Binding Protein 5
chemical_list: D059002:Androgen Receptor Antagonists; D052244:Endocrine Disruptors; D009596:Nitrophenols; D011944:Receptors, Androgen; D022021:Tacrolimus Binding Proteins; D000099159:Tacrolimus Binding Protein 5; C410798:AR protein, human; C024836:4-nitrophenol
keywords: Androgen receptor; Crystal structure; FKBP51; Molecular dynamics simulation; p-Nitrophenol