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

Longying Jiang; Xueke Liu; Xujun Liang; Shuyan Dai; Hudie Wei; Ming Guo; Zhuchu Chen; Desheng Xiao; Yongheng Chen

doi:10.1016/j.csbj.2023.05.026

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

Comput Struct Biotechnol J. 2023 May 27:21:3149-3157. doi: 10.1016/j.csbj.2023.05.026. eCollection 2023.

Authors

Longying Jiang¹, Xueke Liu¹, Xujun Liang¹, Shuyan Dai¹, Hudie Wei¹, Ming Guo¹, Zhuchu Chen¹, Desheng Xiao¹, Yongheng Chen¹

Affiliation

¹ Department of Pathology, NHC Key Laboratory of Cancer Proteomics, State Local Joint Engineering Laboratory for Anticancer Drugs, Department of Oncology, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China.

Abstract

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 regeneration 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.

Keywords: Crystal structure; Farnesoid X receptor; Heterodimer; Inverted repeat DNA; Retinoid X receptor.