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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Abstract
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: | 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 |
| URI: | https://orca.cardiff.ac.uk/id/eprint/146374 |
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