Allosteric signal transduction in FXR/RXR heterodimers bound to steroidal antagonists

Bile acids (BAs) are key signalling steroidal molecules that regulate glucose, lipid and energy homeostasis via interactions with farnesoid X receptor (FXR) and G-protein bile acid receptor 1 (GPBAR1). The FXR functions as an enterohepatic regulator of bile acid homeostasis, cholesterol, lipid, glucose and amino acid metabolism and inflammation [1,2]. Chenodeoxycholic acid (3α,7α-dihydroxy-5β-cholanic acid, CDCA) is the most potent endogenous FXR ligand [3], while lithocholic acid (3α-hydroxy-5β-cholan-24-oic acid, LCA) and its taurine conjugate, taurolitocholic acid (TLCA), activate the GPBAR1 with the highest potency among natural BAs. FXR is a transcription factor from the family of nuclear receptors (NRs). NRs have a conserved folding consisting on an N-terminal DNA-binding domain, which interacts with specific DNA element, connected to the ligand binding domain (LBD). The LBDs is composed by a three-layered α helical sandwich fold, containing 12 α -helices (H1 to H12, Figure 1A-D). The LBD contains a large lipophilic pocket (Ligand Binding Pocket, LBP), which can bind small ligands, triggering the transcriptional switch in the ligand-depended modulation. It also displays the activation function-2 (AF2), a surface (composed by the helices 3, 4, 5 and 12) which can recruit coactivator or corepressor proteins depending on the ligand interacting in the LBP.