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Structure-Guided Approach to Relieving Transcriptional Repression in Resistance to Thyroid Hormone α.

Published version
Peer-reviewed

Type

Article

Change log

Authors

Romartinez-Alonso, Beatriz 
Agostini, Maura 
Jones, Heulyn 
McLellan, Jayde 
Sood, D Eilidh 

Abstract

Mutations in thyroid hormone receptor α (TRα), a ligand-inducible transcription factor, cause resistance to thyroid hormone α (RTHα). This disorder is characterized by tissue-specific hormone refractoriness and hypothyroidism due to the 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. Visualization of the ligand T3 within the crystal structure of a prototypic TRα 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 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.

Description

Keywords

resistance to thyroid hormone, thyroid hormone receptor α, transcriptional repression, Animals, Co-Repressor Proteins, Gene Expression, Genetic Predisposition to Disease, Humans, Mutation, Phenotype, Receptors, Thyroid Hormone, Thyroid Hormone Receptors alpha, Thyroid Hormones, Triiodothyronine

Journal Title

Mol Cell Biol

Conference Name

Journal ISSN

0270-7306
1098-5549

Volume Title

Publisher

Informa UK Limited
Sponsorship
Wellcome Trust (095564/Z/11/Z)
Medical Research Council (MC_UU_12012/5)
Wellcome Trust (210755/Z/18/Z)
European Commission (330183)
Medical Research Council (MC_PC_12012)
NIHR Cambridge Biomedical Research Centre