Structural basis of the farnesoid X receptor/retinoid X receptor heterodimer on inverted repeat DNA

Farnesoid X receptor (FXR) is a ligand-activated transcription factor known as bile acid receptor (BAR). FXR plays critical roles in various biological processes, including metabolism, immune inflammation, liver re-generation and liver carcinogenesis. FXR forms a heterodimer with the retinoid X receptor (RXR) and binds to diverse FXR response elements (FXREs) to exert its various biological functions. However, the mechanism by which the FXR/RXR heterodimer binds the DNA elements remains unclear. In this study, we aimed to use structural, biochemical and bioinformatics analyses to study the mechanism of FXR binding to the typical FXRE, such as the IR1 site, and the heterodimer interactions in the FXR-DBD/RXR-DBD complex. Further biochemical assays showed that RAR, THR and NR4A2 do not form heterodimers with RXR when bound to the IR1 sites, which indicates that IR1 may be a unique binding site for the FXR/RXR heterodimer. Our studies may provide a further understanding of the dimerization specificity of nuclear receptors.& COPY; 2023 The Authors. Published by Elsevier B.V. on behalf of Research Network of Computational and Structural Biotechnology. This is an open access article under the CC BY-NC-ND license (http://creative-commons.org/licenses/by-nc-nd/4.0/).

Automated summary

This study aimed to investigate the mechanism of FXR binding to DNA elements and the heterodimer interactions in the FXR-DBD/RXR-DBD complex through structural, biochemical and bioinformatics analyses. Further biochemical assays showed that RAR, THR, and NR4A2 do not form heterodimers with RXR when bound to the IR1 sites, indicating that IR1 may be a unique binding site for the FXR/RXR heterodimer. These studies could provide a better understanding of dimerization specificity of nuclear receptors.