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Mol Cell Biol ; 42(2): e0036321, 2022 02 17.
Article in English | MEDLINE | ID: mdl-34871063

ABSTRACT

Mutations in thyroid hormone receptor α (TRα), a ligand-inducible transcription factor, cause resistance to thyroid hormone α (RTHα). This disorder is characterized by tissue-specific hormone refractoriness and hypothyroidism due to the inhibition of target gene expression by mutant TRα-corepressor complexes. Using biophysical approaches, we show that RTHα-associated TRα mutants devoid of ligand-dependent transcription activation function unexpectedly retain the ability to bind thyroid hormone. Visualization of the ligand T3 within the crystal structure of a prototypic TRα mutant validates this notion. This finding prompted the synthesis of different thyroid hormone analogues, identifying a lead compound, ES08, which dissociates corepressor from mutant human TRα more efficaciously than T3. ES08 rescues developmental anomalies in a zebrafish model of RTHα and induces target gene expression in TRα mutation-containing cells from an RTHα patient more effectively than T3. Our observations provide proof of principle for developing synthetic ligands that can relieve transcriptional repression by the mutant TRα-corepressor complex for treatment of RTHα.


Subject(s)
Co-Repressor Proteins/genetics , Gene Expression/physiology , Genetic Predisposition to Disease/genetics , Thyroid Hormones/metabolism , Animals , Humans , Mutation/genetics , Phenotype , Receptors, Thyroid Hormone/genetics , Thyroid Hormone Receptors alpha/metabolism , Triiodothyronine/genetics
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