The three subtypes of estrogen-related receptors ERRα, ERRβ, and ERRγ are nuclear receptors mediating metabolic processes in various tissues such as the skeletal muscle, fat tissue, bone, and liver. Although the knowledge on their physiological ligands is limited, they have been implicated as drug targets for important indications including diabetes, cardiovascular diseases, and osteoporosis. As in other nuclear receptors, their ligand binding pocket is buried within the core of the receptor and connected to its surrounding by ligand pathways. Here, we investigated these pathways with conventional molecular dynamics as well as metadynamics simulations to reveal their distribution and their capability to facilitate ligand translocation. Dependent on the ERR subtype and the conformational state of the receptor, we could detect different pathways to be favored. Overall, the results suggested pathways IIIa and IIIb to be favored in the agonistic conformation, while antagonists preferred pathways I, II, and V. Along the pathways, the ligands passed different gating mechanisms of the receptor, including groups of protein residues as well as whole secondary structure elements, to leave the binding site. Even though these pathways are suggested to influence ligand specificity of the receptors and their elucidation might advance rational drug design, they have not yet been studied in ERRs.Communicated by Ramaswamy H. Sarma.
Keywords: ERR; Estrogen-related receptor; channels; metadynamics; molecular dynamics; nuclear receptors; pathways; tunnels.