title: Destabilization of the torsioned conformation of a ligand side chain inverts the LXRβ activity.
abstract: 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.
  
  
  CONCLUSIONS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Dpto. Química Orgánica and UMYMFOR (CONICET-UBA), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Argentina.
authors.forename: Lautaro D
authors.initials: LD
authors.lastname: Álvarez
authors.affiliation: Dpto. Química Biológica and IFIBYNE (UBA-CONICET), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Argentina.
authors.forename: M Virginia
authors.initials: MV
authors.lastname: Dansey
authors.affiliation: Dpto. Química Biológica and IFIBYNE (UBA-CONICET), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Argentina.
authors.forename: Diego Y
authors.initials: DY
authors.lastname: Grinman
authors.affiliation: Dpto. Química Biológica and IFIBYNE (UBA-CONICET), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Argentina.
authors.forename: Daniela
authors.initials: D
authors.lastname: Navalesi
authors.affiliation: Dpto. Química Orgánica and UMYMFOR (CONICET-UBA), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Argentina.
authors.forename: Gisela A
authors.initials: GA
authors.lastname: Samaja
authors.affiliation: Dpto. Química Orgánica and UMYMFOR (CONICET-UBA), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Argentina.
authors.forename: M Celeste
authors.initials: MC
authors.lastname: Del Fueyo
authors.affiliation: Pamgene International BV, 5211HH Den Bosch, The Netherlands.
authors.forename: Niek
authors.initials: N
authors.lastname: Bastiaensen
authors.affiliation: Pamgene International BV, 5211HH Den Bosch, The Netherlands.
authors.forename: René
authors.initials: R
authors.lastname: Houtman
authors.affiliation: Dpto. Química Inorgánica Analítica y Química Física and INQUIMAE (CONICET-UBA), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Argentina.
authors.forename: Darío A
authors.initials: DA
authors.lastname: Estrin
authors.affiliation: Dpto. Química Orgánica and UMYMFOR (CONICET-UBA), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Argentina.
authors.forename: Adriana S
authors.initials: AS
authors.lastname: Veleiro
authors.affiliation: Dpto. Química Biológica and IFIBYNE (UBA-CONICET), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Argentina. Electronic address: apecci@qb.fcen.uba.ar.
authors.forename: Adali
authors.initials: A
authors.lastname: Pecci
authors.affiliation: Dpto. Química Orgánica and UMYMFOR (CONICET-UBA), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Argentina. Electronic address: burton@qo.fcen.uba.ar.
authors.forename: Gerardo
authors.initials: G
authors.lastname: Burton
mesh_terms: D001665:Binding Sites; D002782:Cholestenes / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D008024:Ligands; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*
chemical_list: D002782:Cholestenes; D008024:Ligands; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; C514718:cholestenoic acid
keywords: Cholestenoic acid; Inverse agonism; Liver X receptors; Molecular dynamics