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Structure-Guided Approach to Relieving Transcriptional Repression in Resistance to Thyroid Hormone α.
- Source :
- Molecular & Cellular Biology; Feb2022, Vol. 42 Issue 2, p1-21, 21p
- Publication Year :
- 2022
-
Abstract
- 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. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 02707306
- Volume :
- 42
- Issue :
- 2
- Database :
- Complementary Index
- Journal :
- Molecular & Cellular Biology
- Publication Type :
- Academic Journal
- Accession number :
- 155445529
- Full Text :
- https://doi.org/10.1128/mcb.00363-21