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

Romartinez-Alonso, Beatriz, Agostini, Maura, Jones, Heulyn, McLellan, Jayde, Sood, Deepali, Tomkinson, Nicholas, Marelli, Federica, Gentile, Ilaria, Visser, W. Edward, Schoenmakers, Erik, Fairall, Louise, Privalsky, Martin, Moran, Carla, Persani, Luca, Chatterjee, Krishna and Schwabe, John 2022. Structure-guided approach to relieving transcriptional repression inResistance to Thyroid Hormone α. Molecular and Cellular Biology 42 (2) , e00363-21. 10.1128/MCB.00363-21

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Mutations in thyroid hormone receptor α (TRα), a ligand-inducible transcription factor, cause Resistance to Thyroid Hormone α (RTHα). This disorder is characterised by tissue-specific hormone refractoriness and hypothyroidism, due to 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. Visualisation of ligand (T3) within the crystal structure of a prototypic TRα mutant, validates this notion. This finding prompted 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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Chemistry
Additional Information: This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.
Publisher: American Society for Microbiology
ISSN: 0270-7306
Date of First Compliant Deposit: 6 January 2022
Date of Acceptance: 23 November 2021
Last Modified: 08 May 2023 13:20

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