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Article

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

1
Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Str. 9, 60438 Frankfurt, Germany
2
Structural Genomics Consortium, BMLS, Goethe-University Frankfurt, Max-von-Laue-Str. 15, 60438 Frankfurt, Germany
3
Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Branch for Translational Medicine and Pharmacology TMP, Theodor-Stern-Kai 7, 60596 Frankfurt, Germany
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(22), 8457; https://doi.org/10.3390/ijms21228457
Received: 29 October 2020 / Revised: 6 November 2020 / Accepted: 9 November 2020 / Published: 11 November 2020
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. View Full-Text
Keywords: nuclear receptor; retinoid X receptor; stearic acid; neurodegeneration nuclear receptor; retinoid X receptor; stearic acid; neurodegeneration
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MDPI and ACS Style

Chaikuad, A.; Pollinger, J.; Rühl, M.; Ni, X.; Kilu, W.; Heering, J.; Merk, D. Comprehensive Set of Tertiary Complex Structures and Palmitic Acid Binding Provide Molecular Insights into Ligand Design for RXR Isoforms. Int. J. Mol. Sci. 2020, 21, 8457. https://doi.org/10.3390/ijms21228457

AMA Style

Chaikuad A, Pollinger J, Rühl M, Ni X, Kilu W, Heering J, Merk D. Comprehensive Set of Tertiary Complex Structures and Palmitic Acid Binding Provide Molecular Insights into Ligand Design for RXR Isoforms. International Journal of Molecular Sciences. 2020; 21(22):8457. https://doi.org/10.3390/ijms21228457

Chicago/Turabian Style

Chaikuad, Apirat, Julius Pollinger, Michael Rühl, Xiaomin Ni, Whitney Kilu, Jan Heering, and Daniel Merk. 2020. "Comprehensive Set of Tertiary Complex Structures and Palmitic Acid Binding Provide Molecular Insights into Ligand Design for RXR Isoforms" International Journal of Molecular Sciences 21, no. 22: 8457. https://doi.org/10.3390/ijms21228457

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