Structural insights into the heterodimeric complex of the nuclear receptors FXR and RXR

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--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.

Ligand binding and heterodimerization with retinoid X receptor α (RXRα) induce farnesoid X receptor (FXR) conformational changes affecting coactivator binding

“…In this study, we provide a structural and biochemical characterization of farnesoid X receptor in complex with its obligate heterodimer partner RXR␣. In agreement with previous studies, especially a recent FXR/RXR heterodimer structure with known FXR ligand WAY-362450 (27), we observed that FXR/ RXR heterodimer has the similar heterodimer interface with other RXR heterodimers. Our structural data provide an allosteric mechanism in which communications across the dimer interface, together with the two respective agonists, enhance the affinity of FXR and RXR for binding to individual LXXLL motifs.…”

Nuclear Receptor Metabolism of Bile Acids and Xenobiotics: A Coordinated Detoxification System with Impact on Health and Diseases

“…Even though the FXRα/RXRα heterodimer binds to the consensus IR-1 (IR spaced by 1 base pair) sequence with the highest affinity, this complex also binds to and activates a variety of other FXREs in conjunction with transcriptional co-activators or co-repressors that coordinate either gene activation or repression following post-translational modifications of histones and non-histone proteins. Overviews of FXRα structure, activation, interaction with RXRα, and dynamically-controlled target gene regulation have been published previously [ 22 , 23 , 24 , 25 ].…”

Nuclear Receptors as Multiple Regulators of NLRP3 Inflammasome Function

“…In permissive heterodimers (e.g., PPAR/RXR and LXR/RXR), ligand binding to either partner can mediate their activities. While in non-permissive heterodimers (e.g., VDR/RXR and RAR/RXR), the heterodimer remains silent if only RXR is bound, hence, ligand binding to the partners of RXR is a prerequisite for activation (14,15). While permissive heterodimers seem to be lipid sensors that are regulated by many metabolic pathways (PPAR, LXR), non-permissive ones most likely respond to the classical endocrine steroid (ER) and non-steroid (RAR) factors (16).…”