Structural basis of GC-1 selectivity for thyroid hormone receptor isoforms

To investigate GC-1 specificity, we solved crystal structures and performed molecular dynamics simulations of both isoforms complexed with GC-1. Crystal structures reveal that, in TRα Arg228 is observed in multiple conformations, an effect triggered by the differences in the interactions between GC-1 and Ser277 or the corresponding asparagine (Asn331) of TRβ. The corresponding Arg282 of TRβ is observed in only one single stable conformation, interacting effectively with the ligand. Molecular dynamics support this model: our simulations show that the multiple conformations can be observed for the Arg228 in TRα, in which the ligand interacts either strongly with the ligand or with the Ser277 residue. In contrast, a single stable Arg282 conformation is observed for TRβ, in which it strongly interacts with both GC-1 and the Asn331.Our analysis suggests that the key factors for GC-1 selectivity are the presence of an oxyacetic acid ester oxygen and the absence of the amino group relative to T3. These results shed light into the β-selectivity of GC-1 and may assist the development of new compounds with potential as drug candidates to the treatment of hypercholesterolemia and obesity.Thyroid hormones (TH) have important roles in development and homeostasis. Thyroid receptor (TR) activation occurs when an agonist ligand such as TH or similar compounds binds to a hydrophobic pocket in the core of its ligand-binding domain (LBD). This causes conformational changes which allow DNA bound receptors to interact with coactivators, mediating transcription. TH has a considerable potency as a cholesterol reducer in serum, and stimulates basal metabolic rate, promoting weight loss by the increase of thermogenesis [1,2]. However, deleterious side effects such as tachycardia and atrial arrhythmia are well-documented rendering TH treatment unviable for the treatment of obesity and hypercholesterolemia [3-8].While TH cannot be used to treat dyslipidemias and obesity, TR isoform selective