7NKE

Crystal structure of human RXRalpha ligand binding domain in complex with 2,4-di-tert-butylphenol and a coactivator fragment

Summary for 7NKE

• Entry DOI: 10.2210/pdb7nke/pdb
• Descriptor: Retinoic acid receptor RXR-alpha, Nuclear receptor coactivator 2, 2,4-di~{tert}-butylphenol, ... (5 entities in total)
• Functional Keywords: nuclear receptor, complex, ligand, coactivator, gene regulation
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 58157.43

Authors

Carivenc, C.,Bourguet, W. (deposition date: 2021-02-17, release date: 2022-03-02, Last modification date: 2024-02-07)

Primary citation

Ren, X.M.,Chang, R.C.,Huang, Y.,Amorim Amato, A.,Carivenc, C.,Grimaldi, M.,Kuo, Y.,Balaguer, P.,Bourguet, W.,Blumberg, B.
2,4-Di-tert-butylphenol Induces Adipogenesis in Human Mesenchymal Stem Cells by Activating Retinoid X Receptors.
Endocrinology, 164:-, 2023

PubMed Abstract: 2,4-Di-tert-butylphenol (2,4-DTBP) is an important commercial antioxidant and a toxic natural secondary metabolite that has been detected in humans. However, there is scant information regarding its toxicological effects. We asked whether 2,4-DTBP is a potential obesogen. Using a human mesenchymal stem cell adipogenesis assay, we found that exposure to 2,4-DTBP led to increased lipid accumulation and expression of adipogenic marker genes. Antagonist assays revealed that 2,4-DTBP increased lipid accumulation by activating the peroxisome proliferator-activated receptor (PPAR) γ-retinoid X receptor (RXR) heterodimer. 2,4-DTBP likely activated the PPARγ/RXRα heterodimer by activating RXRα but not directly binding to PPARγ. We confirmed that 2,4-DTBP directly bound to RXRα by solving the crystal structure of this complex, then predicted and demonstrated that related compounds could also activate RXRα. Our study demonstrated that 2,4-DTBP and related chemicals could act as obesogens and endocrine disruptors via RXRs. These data showed that 2,4-DTBP belongs to a family of compounds whose endocrine-disrupting and obesogenic effects can be strongly modulated by their chemical composition. Structure-activity studies such as the present one could help guide the rational development of safer antioxidants that do not interact with important nuclear receptors having broad effects on human development and physiology.

PubMed: 36750942
DOI: 10.1210/endocr/bqad021

Experimental method

X-RAY DIFFRACTION (2.35 Å)