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Article

Flavone and Hydroxyflavones Are Ligands That Bind the Orphan Nuclear Receptor 4A1 (NR4A1)

by
Miok Lee
1,2,
Srijana Upadhyay
1,
Fuada Mariyam
1,
Greg Martin
1,
Amanuel Hailemariam
1,
Kyongbum Lee
3,
Arul Jayaraman
4,
Robert S. Chapkin
5,
Syng-Ook Lee
6 and
Stephen Safe
1,*
1
Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX 77843, USA
2
Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843, USA
3
Department of Chemical and Biological Engineering, Tufts University, Medford, MA 02155, USA
4
Artie McFerrin Department of Chemical Engineering, Texas A&M University, College Station, TX 77843, USA
5
Department of Nutrition, Texas A&M University, College Station, TX 77843, USA
6
Department of Food Science and Technology, Keimyung University, Daegu 42601, Republic of Korea
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2023, 24(9), 8152; https://doi.org/10.3390/ijms24098152
Submission received: 13 April 2023 / Revised: 26 April 2023 / Accepted: 28 April 2023 / Published: 2 May 2023
(This article belongs to the Section Biochemistry)
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Abstract

It was recently reported that the hydroxyflavones quercetin and kaempferol bind the orphan nuclear receptor 4A1 (NR4A1, Nur77) and act as antagonists in cancer cells and tumors, and they inhibit pro-oncogenic NR4A1-regulated genes and pathways. In this study, we investigated the interactions of flavone, six hydroxyflavones, seven dihydroxyflavones, three trihydroxyflavones, two tetrahydroxyflavones, and one pentahydroxyflavone with the ligand-binding domain (LBD) of NR4A1 using direct-binding fluorescence and an isothermal titration calorimetry (ITC) assays. Flavone and the hydroxyflavones bound NR4A1, and their KD values ranged from 0.36 µM for 3,5,7-trihydroxyflavone (galangin) to 45.8 µM for 3′-hydroxyflavone. KD values determined using ITC and KD values for most (15/20) of the hydroxyflavones were decreased compared to those obtained using the fluorescence assay. The results of binding, transactivation and receptor–ligand modeling assays showed that KD values, transactivation data and docking scores for these compounds are highly variable with respect to the number and position of the hydroxyl groups on the flavone backbone structure, suggesting that hydroxyflavones are selective NR4A1 modulators. Nevertheless, the data show that hydroxyflavone-based neutraceuticals are NR4A1 ligands and that some of these compounds can now be repurposed and used to target sub-populations of patients that overexpress NR4A1.
Keywords: flavone; hydroxyflavones; binding; NR4A1 flavone; hydroxyflavones; binding; NR4A1

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MDPI and ACS Style

Lee, M.; Upadhyay, S.; Mariyam, F.; Martin, G.; Hailemariam, A.; Lee, K.; Jayaraman, A.; Chapkin, R.S.; Lee, S.-O.; Safe, S. Flavone and Hydroxyflavones Are Ligands That Bind the Orphan Nuclear Receptor 4A1 (NR4A1). Int. J. Mol. Sci. 2023, 24, 8152. https://doi.org/10.3390/ijms24098152

AMA Style

Lee M, Upadhyay S, Mariyam F, Martin G, Hailemariam A, Lee K, Jayaraman A, Chapkin RS, Lee S-O, Safe S. Flavone and Hydroxyflavones Are Ligands That Bind the Orphan Nuclear Receptor 4A1 (NR4A1). International Journal of Molecular Sciences. 2023; 24(9):8152. https://doi.org/10.3390/ijms24098152

Chicago/Turabian Style

Lee, Miok, Srijana Upadhyay, Fuada Mariyam, Greg Martin, Amanuel Hailemariam, Kyongbum Lee, Arul Jayaraman, Robert S. Chapkin, Syng-Ook Lee, and Stephen Safe. 2023. "Flavone and Hydroxyflavones Are Ligands That Bind the Orphan Nuclear Receptor 4A1 (NR4A1)" International Journal of Molecular Sciences 24, no. 9: 8152. https://doi.org/10.3390/ijms24098152

APA Style

Lee, M., Upadhyay, S., Mariyam, F., Martin, G., Hailemariam, A., Lee, K., Jayaraman, A., Chapkin, R. S., Lee, S.-O., & Safe, S. (2023). Flavone and Hydroxyflavones Are Ligands That Bind the Orphan Nuclear Receptor 4A1 (NR4A1). International Journal of Molecular Sciences, 24(9), 8152. https://doi.org/10.3390/ijms24098152

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