Abstract
SummaryResistance to thyroid hormone (RTH) is a clinical disorder without specific and effective therapeutic strategy, partly due to the lack of structural mechanisms for the defective ligand binding by mutated thyroid hormone receptors (THRs). We herein uncovered the prescription drug roxadustat as a novel THRβ-selective ligand with therapeutic potentials in treating RTH, thereby providing a small molecule tool enabling the first probe into the structural mechanisms of RTH. Despite a wide distribution of the receptor mutation sites, different THRβ mutants induce allosteric conformational modulation on the same His435 residue, which disrupts a critical hydrogen bond required for the binding of thyroid hormones. Interestingly, roxadustat retains hydrophobic interactions with THRβ via its unique phenyl extension, enabling the rescue of the activity of the THRβ mutants. Our study thus reveals a critical receptor allosterism mechanism for RTH by mutant THRβ, providing a new and viable therapeutic strategy for the treatment of RTH.
Highlights
The thyroid hormone receptors (THRs) are nuclear hormone receptors regulated by endogenous thyroid hormones, including the inactive prohormone thyroxine (T4) and the bioactive hormone 3,30,5-triiodothyronine (T3), which are critical for development regulation and metabolic homeostasis
Identification of Roxadustat as a THRb-Selective Ligand In search of novel ligands for THRs, we used THRb ligand-binding domain (LBD) as bait to screen chemical libraries based on AlphaScreen biochemical assay, which determines the efficacy of small molecules in recruiting coregulator peptides to the THRb LBD
Structural Basis for the Recognition of Roxadustat by THRb LBD To determine the molecular basis of the binding selectivity of roxadustat to THRb, we solved the crystal structures of THRb LBD complexed with roxadustat (Table S1)
Summary
The thyroid hormone receptors (THRs) are nuclear hormone receptors regulated by endogenous thyroid hormones, including the inactive prohormone thyroxine (T4) and the bioactive hormone 3,30,5-triiodothyronine (T3), which are critical for development regulation and metabolic homeostasis. Resistance to thyroid hormone (RTH) is a clinical disorder with impaired sensitivity to thyroid hormones at the cellular and tissue level, characterized by elevated thyroid hormone level and a normal or slightly increased thyroid-stimulating hormone level, leading to variable degrees of mental and growth abnormalities (Ortiga-Carvalho et al, 2014; Refetoff et al, 1993). Most RTH mutations identified are located in the ligand-binding domain (LBD) of THRb, leading to resistance to thyroid hormone b (RTHb). The elevated thyroid hormone levels associated with the mutations in THRb or the applications of thyroid hormone analogues can compensate the defective THRb activity, the excess ligands may lead to the over-stimulation of THRa associated with more severe impairment, emphasizing the importance of the development of THRb-selective ligands in treating RTH (Wagner et al, 2001; Martinez et al, 2009).
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