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

Beatriz Romartinez-Alonso, Maura Agostini, Heulyn Jones, Jayde McLellan, Deepali Sood, Nicholas Tomkinson, Federica Marelli, Ilaria Gentile, W. Edward Visser, Erik Schoenmakers, Louise Fairall, Martin Privalsky, Carla Moran, Luca Persani, Krishna Chatterjee, John Schwabe

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3 Citations (Scopus)
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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.

Original languageEnglish
Article numbere00363
Number of pages21
JournalMolecular and Cellular Biology
Issue number2
Early online date6 Dec 2021
Publication statusPublished - 17 Feb 2022


  • cell biology
  • molecular biology
  • thyroid hormone receptor
  • hypothyroidism


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