PUBLICATION
Structure-guided approach to relieving transcriptional repression inResistance to Thyroid Hormone α
- Authors
- Romartinez-Alonso, B., Agostini, M., Jones, H., McLellan, J., Sood, D., Tomkinson, N., Marelli, F., Gentile, I., Visser, W.E., Schoenmakers, E., Fairall, L., Privalsky, M., Moran, C., Persani, L., Chatterjee, K., Schwabe, J.
- ID
- ZDB-PUB-211207-22
- Date
- 2021
- Source
- Molecular and cellular biology 42(2): e0036321 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Animals
- Co-Repressor Proteins/genetics*
- Gene Expression/physiology*
- Genetic Predisposition to Disease/genetics*
- Humans
- Mutation/genetics
- Phenotype
- Receptors, Thyroid Hormone/genetics
- Thyroid Hormone Receptors alpha/metabolism
- Thyroid Hormones/metabolism*
- Triiodothyronine/genetics
- PubMed
- 34871063 Full text @ Mol. Cell. Biol.
Citation
Romartinez-Alonso, B., Agostini, M., Jones, H., McLellan, J., Sood, D., Tomkinson, N., Marelli, F., Gentile, I., Visser, W.E., Schoenmakers, E., Fairall, L., Privalsky, M., Moran, C., Persani, L., Chatterjee, K., Schwabe, J. (2021) Structure-guided approach to relieving transcriptional repression inResistance to Thyroid Hormone α. Molecular and cellular biology. 42(2):e0036321.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping