Destabilization of the torsioned conformation of a ligand side chain inverts the LXRβ activity

Background Liver X receptors (LXRs) are transcription factors activated by cholesterol metabolites containing an oxidized side chain. Due to their ability to regulate lipid metabolism and cholesterol transport, they have become attractive pharmacological targets. LXRs are closely related to DAF-12,...

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Autores principales:	Dansey, Maria Virginia, Grinman, Diego Yair, Estrin, Dario Ariel, Veleiro, Adriana Silvia, Pecci, Adali, Burton, Gerardo
Publicado:	2015
Materias:	Cholestenoic acid Inverse agonism Liver X receptors Molecular dynamics 27 nor 5 cholestenoic acid carboxyl group cholesterol ligand liver X receptor alpha liver X receptor beta methyl group steroid unclassified drug cholestane derivative cholestenoic acid liver X receptor orphan nuclear receptor Article conformational transition gene expression gene expression assay in vitro study ligand binding molecular dynamics molecular stability priority journal protein conformation reporter gene simulation antagonists and inhibitors binding site drug effects gene expression regulation genetics HEK293 cell line HepG2 cell line human metabolism Binding Sites Cholestenes Gene Expression Regulation HEK293 Cells Hep G2 Cells Humans Ligands Orphan Nuclear Receptors
Acceso en línea:	https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_13881981_v1851_n12_p1577_Alvarez http://hdl.handle.net/20.500.12110/paper_13881981_v1851_n12_p1577_Alvarez
Aporte de:	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) de Universidad de Buenos Aires

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spelling	paper:paper_13881981_v1851_n12_p1577_Alvarez2023-06-08T16:13:01Z Destabilization of the torsioned conformation of a ligand side chain inverts the LXRβ activity Dansey, Maria Virginia Grinman, Diego Yair Estrin, Dario Ariel Veleiro, Adriana Silvia Pecci, Adali Burton, Gerardo Cholestenoic acid Inverse agonism Liver X receptors Molecular dynamics 27 nor 5 cholestenoic acid carboxyl group cholesterol ligand liver X receptor alpha liver X receptor beta methyl group steroid unclassified drug cholestane derivative cholestenoic acid liver X receptor orphan nuclear receptor Article conformational transition gene expression gene expression assay in vitro study ligand binding molecular dynamics molecular stability priority journal protein conformation reporter gene simulation antagonists and inhibitors binding site drug effects gene expression regulation genetics HEK293 cell line HepG2 cell line human metabolism Binding Sites Cholestenes Gene Expression Regulation HEK293 Cells Hep G2 Cells Humans Ligands Orphan Nuclear Receptors Background Liver X receptors (LXRs) are transcription factors activated by cholesterol metabolites containing an oxidized side chain. Due to their ability to regulate lipid metabolism and cholesterol transport, they have become attractive pharmacological targets. LXRs are closely related to DAF-12, a nuclear receptor involved in nematode lifespan and regulated by the binding of C-27 steroidal acids. Based on our recent finding that the lack of the C-25 methyl group does not abolish their DAF-12 activity, we evaluated the effect of removing it from the (25R)-cholestenoic acid, a LXR agonist. Methods The binding mode and the molecular basis of action of 27-nor-5-cholestenoic acid were evaluated using molecular dynamics simulations. The biological activity was investigated using reporter gene expression assays and determining the expression levels of endogenous target genes. The in vitro MARCoNI assay was used to analyze the interaction with cofactors. Results 27-Nor-5-cholestenoic acid behaves as an inverse agonist. This correlates with the capacity of the complex to better bind corepressors rather than coactivators. The C-25 methyl moiety would be necessary for the maintenance of a torsioned conformation of the steroid side chain that stabilizes an active LXRβ state. Conclusion We found that a 27-nor analog is able to act as a LXR ligand. Interestingly, this minimal structural change on the steroid triggered a drastic change in the LXR response. General significance Results contribute to improve our understanding on the molecular basis of LXRβ mechanisms of action and provide a new scaffold in the quest for selective LXR modulators. © 2015 Elsevier B.V. All rights reserved. Fil:Dansey, M.V. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Grinman, D.Y. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Estrin, D.A. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Veleiro, A.S. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Pecci, A. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Burton, G. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. 2015 https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_13881981_v1851_n12_p1577_Alvarez http://hdl.handle.net/20.500.12110/paper_13881981_v1851_n12_p1577_Alvarez
institution	Universidad de Buenos Aires
institution_str	I-28
repository_str	R-134
collection	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA)
topic	Cholestenoic acid Inverse agonism Liver X receptors Molecular dynamics 27 nor 5 cholestenoic acid carboxyl group cholesterol ligand liver X receptor alpha liver X receptor beta methyl group steroid unclassified drug cholestane derivative cholestenoic acid liver X receptor orphan nuclear receptor Article conformational transition gene expression gene expression assay in vitro study ligand binding molecular dynamics molecular stability priority journal protein conformation reporter gene simulation antagonists and inhibitors binding site drug effects gene expression regulation genetics HEK293 cell line HepG2 cell line human metabolism Binding Sites Cholestenes Gene Expression Regulation HEK293 Cells Hep G2 Cells Humans Ligands Orphan Nuclear Receptors
spellingShingle	Cholestenoic acid Inverse agonism Liver X receptors Molecular dynamics 27 nor 5 cholestenoic acid carboxyl group cholesterol ligand liver X receptor alpha liver X receptor beta methyl group steroid unclassified drug cholestane derivative cholestenoic acid liver X receptor orphan nuclear receptor Article conformational transition gene expression gene expression assay in vitro study ligand binding molecular dynamics molecular stability priority journal protein conformation reporter gene simulation antagonists and inhibitors binding site drug effects gene expression regulation genetics HEK293 cell line HepG2 cell line human metabolism Binding Sites Cholestenes Gene Expression Regulation HEK293 Cells Hep G2 Cells Humans Ligands Orphan Nuclear Receptors Dansey, Maria Virginia Grinman, Diego Yair Estrin, Dario Ariel Veleiro, Adriana Silvia Pecci, Adali Burton, Gerardo Destabilization of the torsioned conformation of a ligand side chain inverts the LXRβ activity
topic_facet	Cholestenoic acid Inverse agonism Liver X receptors Molecular dynamics 27 nor 5 cholestenoic acid carboxyl group cholesterol ligand liver X receptor alpha liver X receptor beta methyl group steroid unclassified drug cholestane derivative cholestenoic acid liver X receptor orphan nuclear receptor Article conformational transition gene expression gene expression assay in vitro study ligand binding molecular dynamics molecular stability priority journal protein conformation reporter gene simulation antagonists and inhibitors binding site drug effects gene expression regulation genetics HEK293 cell line HepG2 cell line human metabolism Binding Sites Cholestenes Gene Expression Regulation HEK293 Cells Hep G2 Cells Humans Ligands Orphan Nuclear Receptors
description	Background Liver X receptors (LXRs) are transcription factors activated by cholesterol metabolites containing an oxidized side chain. Due to their ability to regulate lipid metabolism and cholesterol transport, they have become attractive pharmacological targets. LXRs are closely related to DAF-12, a nuclear receptor involved in nematode lifespan and regulated by the binding of C-27 steroidal acids. Based on our recent finding that the lack of the C-25 methyl group does not abolish their DAF-12 activity, we evaluated the effect of removing it from the (25R)-cholestenoic acid, a LXR agonist. Methods The binding mode and the molecular basis of action of 27-nor-5-cholestenoic acid were evaluated using molecular dynamics simulations. The biological activity was investigated using reporter gene expression assays and determining the expression levels of endogenous target genes. The in vitro MARCoNI assay was used to analyze the interaction with cofactors. Results 27-Nor-5-cholestenoic acid behaves as an inverse agonist. This correlates with the capacity of the complex to better bind corepressors rather than coactivators. The C-25 methyl moiety would be necessary for the maintenance of a torsioned conformation of the steroid side chain that stabilizes an active LXRβ state. Conclusion We found that a 27-nor analog is able to act as a LXR ligand. Interestingly, this minimal structural change on the steroid triggered a drastic change in the LXR response. General significance Results contribute to improve our understanding on the molecular basis of LXRβ mechanisms of action and provide a new scaffold in the quest for selective LXR modulators. © 2015 Elsevier B.V. All rights reserved.
author	Dansey, Maria Virginia Grinman, Diego Yair Estrin, Dario Ariel Veleiro, Adriana Silvia Pecci, Adali Burton, Gerardo
author_facet	Dansey, Maria Virginia Grinman, Diego Yair Estrin, Dario Ariel Veleiro, Adriana Silvia Pecci, Adali Burton, Gerardo
author_sort	Dansey, Maria Virginia
title	Destabilization of the torsioned conformation of a ligand side chain inverts the LXRβ activity
title_short	Destabilization of the torsioned conformation of a ligand side chain inverts the LXRβ activity
title_full	Destabilization of the torsioned conformation of a ligand side chain inverts the LXRβ activity
title_fullStr	Destabilization of the torsioned conformation of a ligand side chain inverts the LXRβ activity
title_full_unstemmed	Destabilization of the torsioned conformation of a ligand side chain inverts the LXRβ activity
title_sort	destabilization of the torsioned conformation of a ligand side chain inverts the lxrβ activity
publishDate	2015
url	https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_13881981_v1851_n12_p1577_Alvarez http://hdl.handle.net/20.500.12110/paper_13881981_v1851_n12_p1577_Alvarez
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Destabilization of the torsioned conformation of a ligand side chain inverts the LXRβ activity

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