Structure-Guided Approach to Relieving Transcriptional Repression in Resistance to Thyroid Hormone α.

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.

SUBMITTER: Romartinez-Alonso B 

PROVIDER: S-EPMC8852717 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature