Computational insights into the interaction mechanisms of estrogen-related receptor alpha with endogenous ligand cholesterol

Estrogen-related receptor alpha (ERR alpha) has attracted increasing concerns. ERR alpha, orphan nuclear receptor, plays important roles in energy metabolism. Therefore, small molecule agonists of ERR alpha could be a potential therapeutic strategy in the treatment of metabolic diseases such as diabetes. Recently, Wei et al. identified cholesterol as the endogenous agonist of ERR alpha. However, the detailed molecular mechanism of cholesterol bound with ERR alpha remains ambiguous. Thus, in this study molecular docking and molecular dynamics (MD) simulations were performed to characterize how cholesterol affects the behavior of ERR alpha. Based on the results, we found that a proven residue Phe232 and others including Leu228, Glu235, Arg276, and Phe399 were key residues to ligand binding. A hydrogen-bonding interaction between cholesterol and Glu235 ensured the orientation of the ligand in the binding pocket, while hydrophobic interactions between cholesterol and the above-mentioned residues promoted the stability of ERR alpha-cholesterol complex. In the presence of the proliferator-activated receptor gamma coactivator 1 alpha (PGC-1 alpha), the cholesterol-ERR alpha interaction became more stable. Interestingly, we observed that cholesterol facilitated the binding of ERR alpha with its coactivator PGC-1 alpha via stabilizing the conformation of helix 12 and the interaction surface of ERR alpha/PGC-1 alpha. Overall, these findings would be valuable for the future rational design of novel ERR alpha agonists.