Cargando…
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...
Autores principales: | , |
---|---|
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 |
_version_ | 1782428530217320448 |
---|---|
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. |
format | Online Article Text |
id | pubmed-4842504 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | AME Publishing Company |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT wudan ab157theenvironmentalendocrinedisruptorpnitrophenolinteractswithfkbp51apositiveregulatorofandrogenreceptorandinhibitsandrogenreceptorsignalinginhumancells AT wangzhiping ab157theenvironmentalendocrinedisruptorpnitrophenolinteractswithfkbp51apositiveregulatorofandrogenreceptorandinhibitsandrogenreceptorsignalinginhumancells |