Helix 5 mediates ligand-dependent FXR dynamics

The farnesoid X receptor (FXR) is the main target receptor of drug developers working on treatments for non-alcoholic fatty liver disease. It is widely known that FXR exhibits ligand-dependent activation, but the mechanism of activation or features of ligands that correlate with their ability to activate FXR remains unclear. My research seeks to elucidate the patterns of FXR behavior; to accomplish this goal, I have performed triplicate 1 μs classical molecular dynamics simulations on the FXR ligand-binding domain. My set of simulations contains 28 complexes, each with a different bile acid or bile acid homolog docked in the FXR ligand-binding pocket. From the resulting data, we have identified several residues in helix 5 that exhibit different behaviors when in contact with active versus inactive ligands, which may provide insight into how the ligand-binding pocket of FXR undergoes conformational changes which result in the allosteric effects characteristic of nuclear receptor proteins.