Structural insights into the heterodimeric complex of the nuclear receptors FXR and RXR
Zheng, W., Lu, Y., Tian, S., Ma, F., Wei, Y., Xu, S., Li, Y.(2018) J Biol Chem 293: 12535-12541
- PubMed: 29934308 
- DOI: https://doi.org/10.1074/jbc.RA118.004188
- Primary Citation of Related Structures:  
5Z12 - PubMed Abstract: 
Farnesoid X receptor (FXR) is a member of the family of ligand-activated nuclear receptors. FXR plays critical roles in maintaining many metabolic pathways, including bile acid regulation and glucose and lipid homeostasis, and forms a heterodimeric complex with the retinoid X receptor (RXR). Despite the important roles of the FXR/RXR heterodimerization in human physiology, the molecular basis underlying the FXR/RXR interaction is still uncertain in the absence of a complex structure. Here, we report the heterodimeric structure of FXR and RXR in the presence of an FXR agonist (WAY-362450), RXR agonist (9- cis -retinoic acid), and a peptide derived from a steroid receptor coactivator (SRC2), revealing both unique and conserved modes for FXR heterodimerization. We found that the dimerization with RXR induced allosteric conformational changes on the coactivator-binding site of FXR. These changes enhanced the transcriptional activity of FXR by promoting the coactivator binding, thus suggesting a structural basis for the functional permissiveness of the FXR/RXR heterodimer complex. Furthermore, sequence analyses together with functional mutagenesis studies indicated that the helix H10 largely responsible for the dimerization is highly conserved and also critical for the FXR transcriptional activity. Our findings highlight the important roles of RXR heterodimerization in the nuclear receptor signaling, providing a potential framework to develop pharmaceutical agents in treating FXR/RXR-related diseases.
Organizational Affiliation: 
From the State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Fujian 361005, China [email protected].