Cargando…

Comprehensive Set of Tertiary Complex Structures and Palmitic Acid Binding Provide Molecular Insights into Ligand Design for RXR Isoforms

The retinoid X receptor (RXR) is a ligand-sensing transcription factor acting mainly as a universal heterodimer partner for other nuclear receptors. Despite presenting as a potential therapeutic target for cancer and neurodegeneration, adverse effects typically observed for RXR agonists, likely due...

Descripción completa

Detalles Bibliográficos
Autores principales: Chaikuad, Apirat, Pollinger, Julius, Rühl, Michael, Ni, Xiaomin, Kilu, Whitney, Heering, Jan, Merk, Daniel
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7697888/
https://www.ncbi.nlm.nih.gov/pubmed/33187070
http://dx.doi.org/10.3390/ijms21228457
_version_ 1783615702123413504
author Chaikuad, Apirat
Pollinger, Julius
Rühl, Michael
Ni, Xiaomin
Kilu, Whitney
Heering, Jan
Merk, Daniel
author_facet Chaikuad, Apirat
Pollinger, Julius
Rühl, Michael
Ni, Xiaomin
Kilu, Whitney
Heering, Jan
Merk, Daniel
author_sort Chaikuad, Apirat
collection PubMed
description The retinoid X receptor (RXR) is a ligand-sensing transcription factor acting mainly as a universal heterodimer partner for other nuclear receptors. Despite presenting as a potential therapeutic target for cancer and neurodegeneration, adverse effects typically observed for RXR agonists, likely due to the lack of isoform selectivity, limit chemotherapeutic application of currently available RXR ligands. The three human RXR isoforms exhibit different expression patterns; however, they share high sequence similarity, presenting a major obstacle toward the development of subtype-selective ligands. Here, we report the discovery of the saturated fatty acid, palmitic acid, as an RXR ligand and disclose a uniform set of crystal structures of all three RXR isoforms in an active conformation induced by palmitic acid. A structural comparison revealed subtle differences among the RXR subtypes. We also observed an ability of palmitic acid as well as myristic acid and stearic acid to induce recruitment of steroid receptor co-activator 1 to the RXR ligand-binding domain with low micromolar potencies. With the high, millimolar endogenous concentrations of these highly abundant lipids, our results suggest their potential involvement in RXR signaling.
format Online
Article
Text
id pubmed-7697888
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-76978882020-11-29 Comprehensive Set of Tertiary Complex Structures and Palmitic Acid Binding Provide Molecular Insights into Ligand Design for RXR Isoforms Chaikuad, Apirat Pollinger, Julius Rühl, Michael Ni, Xiaomin Kilu, Whitney Heering, Jan Merk, Daniel Int J Mol Sci Article The retinoid X receptor (RXR) is a ligand-sensing transcription factor acting mainly as a universal heterodimer partner for other nuclear receptors. Despite presenting as a potential therapeutic target for cancer and neurodegeneration, adverse effects typically observed for RXR agonists, likely due to the lack of isoform selectivity, limit chemotherapeutic application of currently available RXR ligands. The three human RXR isoforms exhibit different expression patterns; however, they share high sequence similarity, presenting a major obstacle toward the development of subtype-selective ligands. Here, we report the discovery of the saturated fatty acid, palmitic acid, as an RXR ligand and disclose a uniform set of crystal structures of all three RXR isoforms in an active conformation induced by palmitic acid. A structural comparison revealed subtle differences among the RXR subtypes. We also observed an ability of palmitic acid as well as myristic acid and stearic acid to induce recruitment of steroid receptor co-activator 1 to the RXR ligand-binding domain with low micromolar potencies. With the high, millimolar endogenous concentrations of these highly abundant lipids, our results suggest their potential involvement in RXR signaling. MDPI 2020-11-11 /pmc/articles/PMC7697888/ /pubmed/33187070 http://dx.doi.org/10.3390/ijms21228457 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Chaikuad, Apirat
Pollinger, Julius
Rühl, Michael
Ni, Xiaomin
Kilu, Whitney
Heering, Jan
Merk, Daniel
Comprehensive Set of Tertiary Complex Structures and Palmitic Acid Binding Provide Molecular Insights into Ligand Design for RXR Isoforms
title Comprehensive Set of Tertiary Complex Structures and Palmitic Acid Binding Provide Molecular Insights into Ligand Design for RXR Isoforms
title_full Comprehensive Set of Tertiary Complex Structures and Palmitic Acid Binding Provide Molecular Insights into Ligand Design for RXR Isoforms
title_fullStr Comprehensive Set of Tertiary Complex Structures and Palmitic Acid Binding Provide Molecular Insights into Ligand Design for RXR Isoforms
title_full_unstemmed Comprehensive Set of Tertiary Complex Structures and Palmitic Acid Binding Provide Molecular Insights into Ligand Design for RXR Isoforms
title_short Comprehensive Set of Tertiary Complex Structures and Palmitic Acid Binding Provide Molecular Insights into Ligand Design for RXR Isoforms
title_sort comprehensive set of tertiary complex structures and palmitic acid binding provide molecular insights into ligand design for rxr isoforms
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7697888/
https://www.ncbi.nlm.nih.gov/pubmed/33187070
http://dx.doi.org/10.3390/ijms21228457
work_keys_str_mv AT chaikuadapirat comprehensivesetoftertiarycomplexstructuresandpalmiticacidbindingprovidemolecularinsightsintoliganddesignforrxrisoforms
AT pollingerjulius comprehensivesetoftertiarycomplexstructuresandpalmiticacidbindingprovidemolecularinsightsintoliganddesignforrxrisoforms
AT ruhlmichael comprehensivesetoftertiarycomplexstructuresandpalmiticacidbindingprovidemolecularinsightsintoliganddesignforrxrisoforms
AT nixiaomin comprehensivesetoftertiarycomplexstructuresandpalmiticacidbindingprovidemolecularinsightsintoliganddesignforrxrisoforms
AT kiluwhitney comprehensivesetoftertiarycomplexstructuresandpalmiticacidbindingprovidemolecularinsightsintoliganddesignforrxrisoforms
AT heeringjan comprehensivesetoftertiarycomplexstructuresandpalmiticacidbindingprovidemolecularinsightsintoliganddesignforrxrisoforms
AT merkdaniel comprehensivesetoftertiarycomplexstructuresandpalmiticacidbindingprovidemolecularinsightsintoliganddesignforrxrisoforms