Structure-guided approach to relieving transcriptional repression inResistance to Thyroid Hormone α.
Visser, W Edward
Mol Cell Biol
American Society for Microbiology
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Romartinez-Alonso, B., Agostini, M., Jones, H., McLellan, J., Sood, D., Tomkinson, N., Marelli, F., et al. (2021). Structure-guided approach to relieving transcriptional repression inResistance to Thyroid Hormone α.. Mol Cell Biol https://doi.org/10.1128/MCB.00363-21
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.
NIHR Cambridge Biomedical Research Centre
Wellcome Trust (095564/Z/11/Z)
Medical Research Council (MC_UU_12012/5)
External DOI: https://doi.org/10.1128/MCB.00363-21
This record's URL: https://www.repository.cam.ac.uk/handle/1810/331350
Attribution 4.0 International
Licence URL: https://creativecommons.org/licenses/by/4.0/