Fig. 3.

FXR-LBD – ligand/activator (blue)/repressor (light-red) interactions. a (left) The natural FXR agonist CDCA (blue) stabilises α11-α12 (AF2-loop) and α12 (AF2-helix) while the α11 (purple) is partially formed. a (middle, right) Binding of the synthetic agonists fexaramine (yellow) and GW4064 (light blue) has a profound effect and extends the length of the α11. b Binding of ivermectin, destabilises the AF2-loop and in particular the α11 and the Ω-loop. The ivermectin containing FXR-LBD structure is complexed with NCoR-1 and thus represents an antagonistic conformation not fully reflecting ivermectin’s biological activity on FXR. c The partial agonist 1 by disturbing the AF2-loop influences the position of the AF2-helix and thereby affects position, orientation and binding of NCoA. In all structures a–c the α3-α4 loop is depicted in orange and the ligands are shown as sticks. d Overlay of the binding modes of different ligands. Key protein regions affected due to the ligand binding are highlighted with dashed-arcs