Insights into the interaction mechanisms of estrogen-related receptor alpha (ERRα) with ligands via molecular dynamics simulations.

Estrogen-related receptor alpha (ERRα), a member of nuclear receptors (NRs), participates in energy metabolism. Recent experiments identified that several agonists to increase the activity of ERRα, which have a therapeutic effect in improving insulin sensitivity and lowering blood glucose levels. However, the detailed molecular mechanism about how the ligands affect the structure of ERRα remains elusive. To better understand the conformational change of ERRα complexed with agonists and inverse agonists, unbiased molecular dynamics (MD) simulations were performed on the ligand binding domain of ERRα (ERRα-LBD) bound with different ligands. According to the results, the ERRα-agonist interactions were more stable in the presence of the peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α). More importantly, we observed that the binding of inverse agonists would decrease the stability of helix 12 (H12) of ERRα. Moreover, we suggested that Phe232 and Phe414 should be key residues in the interaction pathway from ligands to H12, which provided a possible explanation about how ligands impact the structure of ERRα. These results would provide insights into the design of novel and efficient agonists of ERRα to treat metabolic diabetes.Communicated by Ramaswamy H. Sarma.