A Vitamin D Receptor Selectively Activated by Gemini Analogs Reveals Ligand Dependent and Independent Effects
The bioactive form of vitamin D [1,25(OH)2D3] regulates mineral and bone homeostasis and exerts potent anti-inflammatory and antiproliferative properties through binding to the vitamin D receptor (VDR). The 3D structures of the VDR ligand-binding domain with 1,25(OH)2D3 or gemini analogs unveiled th...
Main Authors: | , , , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Elsevier
2015-02-01
|
Series: | Cell Reports |
Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124714010985 |
id |
doaj-c1ca4632498449e98f431812cd05e383 |
---|---|
record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Tiphaine Huet Gilles Laverny Fabrice Ciesielski Ferdinand Molnár Thanuja Gali Ramamoorthy Anna Y. Belorusova Pierre Antony Noelle Potier Daniel Metzger Dino Moras Natacha Rochel |
spellingShingle |
Tiphaine Huet Gilles Laverny Fabrice Ciesielski Ferdinand Molnár Thanuja Gali Ramamoorthy Anna Y. Belorusova Pierre Antony Noelle Potier Daniel Metzger Dino Moras Natacha Rochel A Vitamin D Receptor Selectively Activated by Gemini Analogs Reveals Ligand Dependent and Independent Effects Cell Reports |
author_facet |
Tiphaine Huet Gilles Laverny Fabrice Ciesielski Ferdinand Molnár Thanuja Gali Ramamoorthy Anna Y. Belorusova Pierre Antony Noelle Potier Daniel Metzger Dino Moras Natacha Rochel |
author_sort |
Tiphaine Huet |
title |
A Vitamin D Receptor Selectively Activated by Gemini Analogs Reveals Ligand Dependent and Independent Effects |
title_short |
A Vitamin D Receptor Selectively Activated by Gemini Analogs Reveals Ligand Dependent and Independent Effects |
title_full |
A Vitamin D Receptor Selectively Activated by Gemini Analogs Reveals Ligand Dependent and Independent Effects |
title_fullStr |
A Vitamin D Receptor Selectively Activated by Gemini Analogs Reveals Ligand Dependent and Independent Effects |
title_full_unstemmed |
A Vitamin D Receptor Selectively Activated by Gemini Analogs Reveals Ligand Dependent and Independent Effects |
title_sort |
vitamin d receptor selectively activated by gemini analogs reveals ligand dependent and independent effects |
publisher |
Elsevier |
series |
Cell Reports |
issn |
2211-1247 |
publishDate |
2015-02-01 |
description |
The bioactive form of vitamin D [1,25(OH)2D3] regulates mineral and bone homeostasis and exerts potent anti-inflammatory and antiproliferative properties through binding to the vitamin D receptor (VDR). The 3D structures of the VDR ligand-binding domain with 1,25(OH)2D3 or gemini analogs unveiled the molecular mechanism underlying ligand recognition. On the basis of structure-function correlations, we generated a point-mutated VDR (VDRgem) that is unresponsive to 1,25(OH)2D3, but the activity of which is efficiently induced by the gemini ligands. Moreover, we show that many VDR target genes are repressed by unliganded VDRgem and that mineral ion and bone homeostasis are more impaired in VDRgem mice than in VDR null mice, demonstrating that mutations abolishing VDR ligand binding result in more severe skeletal defects than VDR null mutations. As gemini ligands induce VDRgem transcriptional activity in mice and normalize their serum calcium levels, VDRgem is a powerful tool to further unravel both liganded and unliganded VDR signaling. |
url |
http://www.sciencedirect.com/science/article/pii/S2211124714010985 |
work_keys_str_mv |
AT tiphainehuet avitamindreceptorselectivelyactivatedbygeminianalogsrevealsliganddependentandindependenteffects AT gilleslaverny avitamindreceptorselectivelyactivatedbygeminianalogsrevealsliganddependentandindependenteffects AT fabriceciesielski avitamindreceptorselectivelyactivatedbygeminianalogsrevealsliganddependentandindependenteffects AT ferdinandmolnar avitamindreceptorselectivelyactivatedbygeminianalogsrevealsliganddependentandindependenteffects AT thanujagaliramamoorthy avitamindreceptorselectivelyactivatedbygeminianalogsrevealsliganddependentandindependenteffects AT annaybelorusova avitamindreceptorselectivelyactivatedbygeminianalogsrevealsliganddependentandindependenteffects AT pierreantony avitamindreceptorselectivelyactivatedbygeminianalogsrevealsliganddependentandindependenteffects AT noellepotier avitamindreceptorselectivelyactivatedbygeminianalogsrevealsliganddependentandindependenteffects AT danielmetzger avitamindreceptorselectivelyactivatedbygeminianalogsrevealsliganddependentandindependenteffects AT dinomoras avitamindreceptorselectivelyactivatedbygeminianalogsrevealsliganddependentandindependenteffects AT natacharochel avitamindreceptorselectivelyactivatedbygeminianalogsrevealsliganddependentandindependenteffects AT tiphainehuet vitamindreceptorselectivelyactivatedbygeminianalogsrevealsliganddependentandindependenteffects AT gilleslaverny vitamindreceptorselectivelyactivatedbygeminianalogsrevealsliganddependentandindependenteffects AT fabriceciesielski vitamindreceptorselectivelyactivatedbygeminianalogsrevealsliganddependentandindependenteffects AT ferdinandmolnar vitamindreceptorselectivelyactivatedbygeminianalogsrevealsliganddependentandindependenteffects AT thanujagaliramamoorthy vitamindreceptorselectivelyactivatedbygeminianalogsrevealsliganddependentandindependenteffects AT annaybelorusova vitamindreceptorselectivelyactivatedbygeminianalogsrevealsliganddependentandindependenteffects AT pierreantony vitamindreceptorselectivelyactivatedbygeminianalogsrevealsliganddependentandindependenteffects AT noellepotier vitamindreceptorselectivelyactivatedbygeminianalogsrevealsliganddependentandindependenteffects AT danielmetzger vitamindreceptorselectivelyactivatedbygeminianalogsrevealsliganddependentandindependenteffects AT dinomoras vitamindreceptorselectivelyactivatedbygeminianalogsrevealsliganddependentandindependenteffects AT natacharochel vitamindreceptorselectivelyactivatedbygeminianalogsrevealsliganddependentandindependenteffects |
_version_ |
1725862574507950080 |
spelling |
doaj-c1ca4632498449e98f431812cd05e3832020-11-24T21:55:28ZengElsevierCell Reports2211-12472015-02-0110451652610.1016/j.celrep.2014.12.045A Vitamin D Receptor Selectively Activated by Gemini Analogs Reveals Ligand Dependent and Independent EffectsTiphaine Huet0Gilles Laverny1Fabrice Ciesielski2Ferdinand Molnár3Thanuja Gali Ramamoorthy4Anna Y. Belorusova5Pierre Antony6Noelle Potier7Daniel Metzger8Dino Moras9Natacha Rochel10Department of Integrative Structural Biology, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut National de la Santé et de la Recherche Médicale (INSERM) U964, Centre National de la Recherche Scientifique (CNRS) UMR 7104, Université de Strasbourg, 67404 Illkirch, FranceDepartment of Functional Genomics and Cancer, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut National de la Santé et de la Recherche Médicale (INSERM) U964, Centre National de la Recherche Scientifique (CNRS) UMR 7104, Université de Strasbourg, 67404 Illkirch, FranceDepartment of Integrative Structural Biology, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut National de la Santé et de la Recherche Médicale (INSERM) U964, Centre National de la Recherche Scientifique (CNRS) UMR 7104, Université de Strasbourg, 67404 Illkirch, FranceDepartment of Integrative Structural Biology, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut National de la Santé et de la Recherche Médicale (INSERM) U964, Centre National de la Recherche Scientifique (CNRS) UMR 7104, Université de Strasbourg, 67404 Illkirch, FranceDepartment of Functional Genomics and Cancer, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut National de la Santé et de la Recherche Médicale (INSERM) U964, Centre National de la Recherche Scientifique (CNRS) UMR 7104, Université de Strasbourg, 67404 Illkirch, FranceDepartment of Integrative Structural Biology, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut National de la Santé et de la Recherche Médicale (INSERM) U964, Centre National de la Recherche Scientifique (CNRS) UMR 7104, Université de Strasbourg, 67404 Illkirch, FranceDepartment of Integrative Structural Biology, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut National de la Santé et de la Recherche Médicale (INSERM) U964, Centre National de la Recherche Scientifique (CNRS) UMR 7104, Université de Strasbourg, 67404 Illkirch, FranceInstitut de Chimie LC3-CNRS-UMR 7177, 67008 Strasbourg, FranceDepartment of Functional Genomics and Cancer, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut National de la Santé et de la Recherche Médicale (INSERM) U964, Centre National de la Recherche Scientifique (CNRS) UMR 7104, Université de Strasbourg, 67404 Illkirch, FranceDepartment of Integrative Structural Biology, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut National de la Santé et de la Recherche Médicale (INSERM) U964, Centre National de la Recherche Scientifique (CNRS) UMR 7104, Université de Strasbourg, 67404 Illkirch, FranceDepartment of Integrative Structural Biology, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut National de la Santé et de la Recherche Médicale (INSERM) U964, Centre National de la Recherche Scientifique (CNRS) UMR 7104, Université de Strasbourg, 67404 Illkirch, FranceThe bioactive form of vitamin D [1,25(OH)2D3] regulates mineral and bone homeostasis and exerts potent anti-inflammatory and antiproliferative properties through binding to the vitamin D receptor (VDR). The 3D structures of the VDR ligand-binding domain with 1,25(OH)2D3 or gemini analogs unveiled the molecular mechanism underlying ligand recognition. On the basis of structure-function correlations, we generated a point-mutated VDR (VDRgem) that is unresponsive to 1,25(OH)2D3, but the activity of which is efficiently induced by the gemini ligands. Moreover, we show that many VDR target genes are repressed by unliganded VDRgem and that mineral ion and bone homeostasis are more impaired in VDRgem mice than in VDR null mice, demonstrating that mutations abolishing VDR ligand binding result in more severe skeletal defects than VDR null mutations. As gemini ligands induce VDRgem transcriptional activity in mice and normalize their serum calcium levels, VDRgem is a powerful tool to further unravel both liganded and unliganded VDR signaling.http://www.sciencedirect.com/science/article/pii/S2211124714010985 |