Structural insights into thyroid hormone receptors

Abstract Thyroid hormone receptors (TRs) are essential components of the endocrine system, mediating the cellular effects of thyroid hormones. The two TR genes, THRA and THRB, encode four isoforms, with TRα1 and TRβ1 being the most prevalent. TRs are ligand-dependent transcription factors and members of the nuclear receptor superfamily, indispensable for human growth, development and metabolism. Dysfunctional TR signaling can lead to conditions like resistance to thyroid hormone (RTH) syndrome, thyroid cancer, and metabolic disorders. Structurally, TRs comprise several domains: a variable N-terminal domain, a conserved DNA-binding domain, and a ligand-binding domain that mediates interaction with hormones and transcriptional coregulators. TRs predominantly function as heterodimers with the retinoid X receptor (RXR), binding to thyroid hormone response elements (TREs) in target genes to regulate their transcription. This review examines the structural studies on TRs, primarily performed through X-ray crystallography, that have provided detailed insights into TR functions, including DNA recognition, ligand binding, and coregulator interactions. We also discuss how these findings have deepened our understanding of TR mechanisms and contributed to the interpretation of pathogenic mutations.