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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.
Highlights
Farnesoid X receptor (FXR) is a member of the family of ligand-activated nuclear receptors
We found that the dimerization with retinoid X receptor (RXR) induced allosteric conformational changes on the coactivator-binding site of FXR
The presence of the RXR␣ moiety in the heterodimer further increased FXR’s affinity for the SRC2 coactivator motif (Fig. 1b). These results on the purified ligand-binding domain (LBD) of FXR and RXR are consistent with the permissive nature of the FXR/RXR heterodimer, highlighting the importance of the RXR heterodimerization for FXR ligand binding and coactivator recruitment
Summary
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). Expressed in the liver, intestine, kidney, and adrenals, FXR is responsible for the regulation of the specific target genes involved in biological processes including bile acids, glucose, and lipid homeostasis and thereby has become an important drug target for the treatment of many FXR-mediated diseases. In addition to the coregulator recruitment, the activity of FXR is modulated by the heterodimerization with the retinoid X receptor (RXR), receptors for the vitamin A metabolite 9-cis-retinoic acid (9-cis-RA), providing an additional level of regulation of the FXR signaling pathways [10]. Crystal structures of the many heterodimers structures, such as PPAR/RXR [13], retinoic acid receptor/RXR [14], LXR/RXR [15], PXR/RXR [16], constitutive androstane receptor (CAR)/ RXR [17, 18], and thyroid-hormone receptor/RXR [19, 20] heterodimers, have revealed a common mode of dimerization
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