Abstract
Estrogen-related receptors (ERRs) are orphan nuclear receptors critical to the regulation of energy metabolism, mitochondrial biogenesis, and tissue-specific transcriptional programs. This review provides a comprehensive structural analysis of ERR isoforms (ERRα, ERRβ, and ERRγ), emphasizing insights from X-ray crystallography and NMR studies. We discuss the ligand-binding domains (LBDs), coactivator and corepressor interactions, and the molecular mechanisms underlying ligand-induced agonism or antagonism. Structural comparisons with estrogen receptors (ERs) reveal key amino acid determinants for ligand selectivity and functional activity. Furthermore, we highlight the development of isoform-selective synthetic ligands, including inverse agonists such as GSK5182, DN200434, and DN201000, with therapeutic potential in metabolic, neurodegenerative, and oncologic diseases. This synthesis of structural data provides a framework for rational drug design targeting ERRs, supporting the development of selective modulators to manipulate ERR signaling in a tissue- and disease-specific manner.