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Publication Abstract from PubMed

Mutations in thyroid hormone receptor alpha (TRalpha), a ligand-inducible transcription factor, cause Resistance to Thyroid Hormone alpha (RTHalpha). This disorder is characterised by tissue-specific hormone refractoriness and hypothyroidism, due to inhibition of target gene expression by mutant TRalpha-corepressor complexes. Using biophysical approaches, we show that RTHalpha-associated TRalpha 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 TRalpha mutant, validates this notion. This finding prompted synthesis of different thyroid hormone analogues, identifying a lead compound (ES08) which dissociates corepressor from mutant human TRalpha more efficaciously than T3. ES08 rescues developmental anomalies in a zebrafish model of RTHalpha and induces target gene expression in TRalpha mutation-containing cells from an RTHalpha patient, more effectively than T3. Our observations provide proof-of-principle for developing synthetic ligands that can relieve transcriptional repression by the mutant TRalpha-corepressor complex, for treatment of RTHalpha.

Structure-guided approach to relieving transcriptional repression inResistance to Thyroid Hormone alpha.,Romartinez-Alonso B, Agostini M, Jones H, McLellan J, Sood D, Tomkinson N, Marelli F, Gentile I, Visser WE, Schoenmakers E, Fairall L, Privalsky M, Moran C, Persani L, Chatterjee K, Schwabe J Mol Cell Biol. 2021 Dec 6:MCB0036321. doi: 10.1128/MCB.00363-21. PMID:34871063^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.