Comprehensive Set of Tertiary Complex Structures and Palmitic Acid Binding Provide Molecular Insights into Ligand
Apirat Chaikuad1,2, Julius Pollinger1, Michael Rühl1
1Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Str. 9, 60438 Frankfurt, Germany.
Abstract:
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.
Insights
Saturated fatty acids like palmitic acid bind to retinoid X receptor (RXR) isoforms. This discovery offers new avenues for developing selective RXR-targeting cancer and neurodegeneration therapies.
Area of Science:
- Biochemistry
- Molecular Biology
- Structural Biology
Background:
- Retinoid X receptor (RXR) is a crucial transcription factor and therapeutic target for cancer and neurodegeneration.
- Current RXR ligands lack isoform selectivity, leading to adverse effects and limiting therapeutic applications.
- High sequence similarity among RXR isoforms hinders the development of subtype-selective drugs.
Purpose of the Study:
- To identify novel ligands for retinoid X receptor (RXR) isoforms.
- To investigate the structural basis of RXR isoform activation by saturated fatty acids.
- To explore the potential of saturated fatty acids in modulating RXR signaling pathways.
Main Methods:
- X-ray crystallography to determine the structures of all three human RXR isoforms bound to palmitic acid.
- Structural comparison of RXR isoforms to identify subtle differences.
- Coactivator recruitment assays to assess the functional activity of fatty acids on RXR.
Main Results:
- Palmitic acid, a saturated fatty acid, was identified as a novel RXR ligand.
- Crystal structures revealed all three RXR isoforms in an active conformation induced by palmitic acid.
- Palmitic acid, myristic acid, and stearic acid induced coactivator recruitment to RXR ligand-binding domain with low micromolar potency.
Conclusions:
- Saturated fatty acids, such as palmitic acid, can act as endogenous ligands for RXR.
- The identified RXR-fatty acid interactions provide structural insights into RXR activation.
- These findings suggest a potential physiological role for abundant lipids in regulating RXR signaling, opening new therapeutic strategies.
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