Abstract
Nuclear receptor farnesoid X receptor (FXR) functions as the major bile acid sensor coordinating cholesterol metabolism, lipid homeostasis, and absorption of dietary fats and vitamins. Because of its central role in metabolism, FXR represents an important drug target to manage metabolic and other diseases, such as primary biliary cirrhosis and nonalcoholic steatohepatitis. FXR and nuclear receptor retinoid X receptor α (RXRα) form a heterodimer that controls the expression of numerous downstream genes. To date, the structural basis and functional consequences of the FXR/RXR heterodimer interaction have remained unclear. Herein, we present the crystal structures of the heterodimeric complex formed between the ligand-binding domains of human FXR and RXRα. We show that both FXR and RXR bind to the transcriptional coregulator steroid receptor coactivator 1 with higher affinity when they are part of the heterodimer complex than when they are in their respective monomeric states. Furthermore, structural comparisons of the FXR/RXRα heterodimers and the FXR monomers bound with different ligands indicated that both heterodimerization and ligand binding induce conformational changes in the C terminus of helix 11 in FXR that affect the stability of the coactivator binding surface and the coactivator binding in FXR. In summary, our findings shed light on the allosteric signal transduction in the FXR/RXR heterodimer, which may be utilized for future drug development targeting FXR.
Highlights
Nuclear receptor farnesoid X receptor (FXR) functions as the major bile acid sensor coordinating cholesterol metabolism, lipid homeostasis, and absorption of dietary fats and vitamins
Structural comparisons of the FXR/ RXR␣ heterodimers and the FXR monomers bound with different ligands indicated that both heterodimerization and ligand binding induce conformational changes in the C terminus of helix 11 in FXR that affect the stability of the coactivator binding surface and the coactivator binding in FXR
The purified hFXR/RXR␣–ligand-binding domain (LBD) heterodimer was crystallized in complex with FXR agonists (HNC143, HNC180, or GW4064), RXR natural ligand 9-cis-retinoic acid (9cRA), and a synthetic peptide derived from the coactivator steroid receptor coactivator 1 (SRC1)–2 containing a single LXXLL motif
Summary
The hFXR–LBD was crystallized in the presence of FXR agonists (HNC143 and HNC180) and SRC1 (fragment 741–761) with one LXXLL motif. The structures of the hFXR/RXR␣ LBD heterodimer complexes contain six components: two receptor LBDs, their respective ligands, and two SRC1 peptides (Fig. 1a). The FXR and RXR␣ ligands occupy their respective ligandbinding pockets, and both receptors adopt the active configuration, such that the H12 is folded against the main body of the LBD. This conformation generates a recognition surface (AF2 surface) constituted by mostly hydrophobic residues from H3, H4, and H12 of FXR and RXR␣, which allow one SRC1 peptide to bind to each receptor. Two coactivator peptides fold as a two-turn ␣-helix in the heterodimer complex with the hydrophobic side chains (LXXLL) packed against the agonist-induced FXR and RXR␣ surfaces
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