Structure-Guided Approach to Relieving Transcriptional Repression in Resistance to Thyroid Hormone α
Mutations in thyroid hormone receptor a (TRα), a ligand-inducible transcription factor, cause resistance to thyroid hormone a (RTHα). 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.
Our research is supported by the Wellcome Trust (Investigator Award 210755/Z/18/Z to K.C.; Investigator Award 100237/Z/12/Z to J.W.R.S.) and the NIHR Cambridge Biomedical Research Centre (C.M. and K.C.). Zebrafish studies (F.M. and L.P.) were supported by Ricerca Corrente Funds (Transtir, 05C501_2015) from the Istituto Auxologico Italiano and by an unrestricted research grant from Sandoz, Italy. W.E.V. was supported by a Marie Curie Intra-European Fellowship (330183) and a research grant from the Foundation for Development of Internal Medicine in Europe.
CitationRomartinez-Alonso, Beatriz, et al. "Structure-Guided Approach to Relieving Transcriptional Repression in Resistance to Thyroid Hormone α." Molecular and cellular biology 42.2 (2021): e00363-21.
Author affiliationLeicester Institute of Structural and Chemical Biology
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