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AB157. The environmental endocrine disruptor p-nitrophenol interacts with FKBP51, a positive regulator of androgen receptor and inhibits androgen receptor signaling in human cells

OBJECTIVE: Although it was shown that p-nitrophenol is anti-androgenic in vivo, the molecular details of how p-nitrophenol inhibits AR signaling are still not quite clear. In this report, we want to figure out this signaling in human cells. METHODS: (I) Cell viability assay; (II) endogenous expressi...

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Detalles Bibliográficos
Autores principales: Wu, Dan, Wang, Zhiping
Formato: Online Artículo Texto
Lenguaje:English
Publicado: AME Publishing Company 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4842504/
http://dx.doi.org/10.21037/tau.2016.s157
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author Wu, Dan
Wang, Zhiping
author_facet Wu, Dan
Wang, Zhiping
author_sort Wu, Dan
collection PubMed
description OBJECTIVE: Although it was shown that p-nitrophenol is anti-androgenic in vivo, the molecular details of how p-nitrophenol inhibits AR signaling are still not quite clear. In this report, we want to figure out this signaling in human cells. METHODS: (I) Cell viability assay; (II) endogenous expression of androgen-activated genes; (III) expression, and purification of the FK1 domain of FKBP51; (IV) fluorescence quenching assay; (V) crystallization and data collection; (VI) structure determination; (VII) molecular dynamics (MD) simulation; (VIII) the free energy calculation. RESULTS: we show that p-nitrophenol inhibits the androgen dependent cell growth and down-regulates the expression levels of AR target genes. Furthermore, we identified that p-nitrophenol binds with micromolar affinity to the Hsp90 co-chaperone FKBP51, a protein essential for AR activation. Crystal structure of FKBP51 in complex with p-nitrophenol revealed that p-nitrophenol occupies a hydrophobic pocket of FKBP51 that is vital for AR activity enhancement. Molecular dynamics simulation indicate that p-nitrophenol is stably bound to the FKBP51 pocket and the hotspot residues that involved p-nitrophenol binding are mainly hydrophobic and overlap with the AR interaction site. CONCLUSIONS: our results demonstrate the anti-androgenic activity of p-nitrophenol in human cells and illustrate the binding mechanism between p-nitrophenol and its potential molecular target FKBP51, providing guidelines for assessing the long term health risks of p-nitrophenol and its derivatives.
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spelling pubmed-48425042016-05-09 AB157. The environmental endocrine disruptor p-nitrophenol interacts with FKBP51, a positive regulator of androgen receptor and inhibits androgen receptor signaling in human cells Wu, Dan Wang, Zhiping Transl Androl Urol Printed Abstracts OBJECTIVE: Although it was shown that p-nitrophenol is anti-androgenic in vivo, the molecular details of how p-nitrophenol inhibits AR signaling are still not quite clear. In this report, we want to figure out this signaling in human cells. METHODS: (I) Cell viability assay; (II) endogenous expression of androgen-activated genes; (III) expression, and purification of the FK1 domain of FKBP51; (IV) fluorescence quenching assay; (V) crystallization and data collection; (VI) structure determination; (VII) molecular dynamics (MD) simulation; (VIII) the free energy calculation. RESULTS: we show that p-nitrophenol inhibits the androgen dependent cell growth and down-regulates the expression levels of AR target genes. Furthermore, we identified that p-nitrophenol binds with micromolar affinity to the Hsp90 co-chaperone FKBP51, a protein essential for AR activation. Crystal structure of FKBP51 in complex with p-nitrophenol revealed that p-nitrophenol occupies a hydrophobic pocket of FKBP51 that is vital for AR activity enhancement. Molecular dynamics simulation indicate that p-nitrophenol is stably bound to the FKBP51 pocket and the hotspot residues that involved p-nitrophenol binding are mainly hydrophobic and overlap with the AR interaction site. CONCLUSIONS: our results demonstrate the anti-androgenic activity of p-nitrophenol in human cells and illustrate the binding mechanism between p-nitrophenol and its potential molecular target FKBP51, providing guidelines for assessing the long term health risks of p-nitrophenol and its derivatives. AME Publishing Company 2016-04 /pmc/articles/PMC4842504/ http://dx.doi.org/10.21037/tau.2016.s157 Text en 2016 Translational Andrology and Urology. All rights reserved.
spellingShingle Printed Abstracts
Wu, Dan
Wang, Zhiping
AB157. The environmental endocrine disruptor p-nitrophenol interacts with FKBP51, a positive regulator of androgen receptor and inhibits androgen receptor signaling in human cells
title AB157. The environmental endocrine disruptor p-nitrophenol interacts with FKBP51, a positive regulator of androgen receptor and inhibits androgen receptor signaling in human cells
title_full AB157. The environmental endocrine disruptor p-nitrophenol interacts with FKBP51, a positive regulator of androgen receptor and inhibits androgen receptor signaling in human cells
title_fullStr AB157. The environmental endocrine disruptor p-nitrophenol interacts with FKBP51, a positive regulator of androgen receptor and inhibits androgen receptor signaling in human cells
title_full_unstemmed AB157. The environmental endocrine disruptor p-nitrophenol interacts with FKBP51, a positive regulator of androgen receptor and inhibits androgen receptor signaling in human cells
title_short AB157. The environmental endocrine disruptor p-nitrophenol interacts with FKBP51, a positive regulator of androgen receptor and inhibits androgen receptor signaling in human cells
title_sort ab157. the environmental endocrine disruptor p-nitrophenol interacts with fkbp51, a positive regulator of androgen receptor and inhibits androgen receptor signaling in human cells
topic Printed Abstracts
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4842504/
http://dx.doi.org/10.21037/tau.2016.s157
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