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.
Structure-guided approach to relieving transcriptional repression in resistance to thyroid hormone α / B. Romartinez-Alonso, M. Agostini, H. Jones, J. Mclellan, D. Eilidh Sood, N. Tomkinson, F. Marelli, I. Gentile, W. Edward Visser, E. Schoenmakers, L. Fairall, M. Privalsky, C. Moran, L. Persani, K. Chatterjee, J.W.R. Schwabe. - In: MOLECULAR AND CELLULAR BIOLOGY. - ISSN 0270-7306. - 42:2(2022 Feb), pp. e00363-21.1-e00363-21.21. [10.1128/mcb.00363-21]
Structure-guided approach to relieving transcriptional repression in resistance to thyroid hormone α
F. MarelliInvestigation
;I. GentileInvestigation
;L. PersaniWriting – Review & Editing
;
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.File | Dimensione | Formato | |
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