Amber Molecular Dynamics Simulations Display Ligand Induced Conformational Changes in Coregulator Binding Surface of Nuclear Receptor FXR

Nuclear receptors (NRs) are cellular proteins that regulate gene expression and serve as targets for 10-20% of all FDA approved medications. When bound by agonists, nuclear receptors adopt an active conformation that allows for a coactivator peptide to bind the NR, turning on gene transcription. Differences in coactivator recruitment may result in variant downstream effects, such as medication adverse effects, induced by altered gene expression. The Farnesoid X Receptor (FXR) is a NR primarily expressed in the liver. Ligands such as bile acids bind FXR endogenously in the human body, but prescription medications such as obeticholic acid target FXR for the treatment of primary biliary cholangitis. However, obeticholic acid has been associated with serious liver injury among patients being treated with the medication. We therefore utilized Amber molecular dynamics simulations to determine structural features induced in FXR in the presence of obeticholic acid and additional ligands; these structural features were assessed for correlation to stability of binding of coactivators NCOA2_609 and MED1_604 to FXR. Key structural differences in FXR helices 3, 11, and 12 are seen among various agonists. Most notably, ligand interactions with helix 11 residue, His447, and intermolecular interactions between His447 and helix 12 Trp469 may contribute to specific coactivator binding stability. By investigating these structural changes and how they impact coactivator binding, smarter drug design may be employed in the future to optimize medications with efficacious profiles and fewer side effects.