Allosteric Regulation of Coregulator Recruitment in FXR

The farnesoid x receptor (FXRα,NR1H4) is a ligand regulated transcription factor that plays a role in bile acid, carbohydrate, and lipid metabolism. The natural ligands of FXR are bile acids, a diverse class of cholesterol-derived steroid acids. As a member of the nuclear receptor (NR) superfamily, FXR is comprised of modular domains, including a DNA binding domain (DBD) that is linked to a ligand binding domain (LBD) by a flexible hinge. The LBD contains the activation function 2 (AF-2) surface that is the site of coregulator binding. Coregulators are an important class of proteins that are recruited to transcriptional complexes and promote up/down regulation of genes of interest by targeting chromatin. While it has been shown that coregulator recruitment to is modulated in a ligand-specific manner, it is not understood how minor modifications on the bile acid scaffold drive differences in coregulator recruitment, and more broadly, diverse transcriptional outcomes. The goal of this project is to understand how minor differences in ligand structure gives rise to preferences in coregulator recruitment to FXR. To investigate this phenomenon, we are using dual luciferase assays and binding experiments to determine how various coregulators are utilized by FXR for transcription in the presence of multiple bile acids.