Structure-guided approach to relieving transcriptional repression inResistance to Thyroid Hormone α

Romartinez-Alonso, Beatriz and Agostini, Maura and Jones, Heulyn and McLellan, Jayde and Sood, Deepali and Tomkinson, Nicholas and Marelli, Federica and Gentile, Ilaria and Visser, W. Edward and Schoenmakers, Erik and Fairall, Louise and Privalsky, Martin and Moran, Carla and Persani, Luca and Chatterjee, Krishna and Schwabe, John (2022) Structure-guided approach to relieving transcriptional repression inResistance to Thyroid Hormone α. Molecular and Cellular Biology, 42 (2). e00363. ISSN 0270-7306 (

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Mutations in thyroid hormone receptor a (TRa), a ligand-inducible transcription factor, cause resistance to thyroid hormone a (RTHa). This disorder is characterized by tissue-specific hormone refractoriness and hypothyroidism due to the inhibition of target gene expression by mutant TRa-corepressor complexes. Using biophysical approaches, we show that RTHa-associated TRa 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 TRa 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 TRa more efficaciously than T3. ES08 rescues developmental anomalies in a zebrafish model of RTHa and induces target gene expression in TRa mutation-containing cells from an RTHa patient more effectively than T3. Our observations provide proof of principle for developing synthetic ligands that can relieve transcriptional repression by the mutant TRa-corepressor complex for treatment of RTHa.