Leicester Institute of Structural and Chemical Biology, Department of Molecular and Cell Biology, University of Leicestergrid.9918.9, Leicester, United Kingdom.
Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridgegrid.5335.0, Cambridge, United Kingdom.
Mol Cell Biol. 2022 Feb 17;42(2):e0036321. doi: 10.1128/MCB.00363-21. Epub 2021 Dec 6.
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.
甲状腺激素受体 α (TRα) 突变是一种配体诱导型转录因子，可导致甲状腺激素 α 抵抗 (RTHα)。这种疾病的特征是组织特异性激素抵抗和甲状腺功能减退，这是由于突变 TRα-共抑制物复合物抑制靶基因表达所致。我们使用生物物理方法表明，缺乏配体依赖性转录激活功能的 RTHα 相关 TRα 突变体出人意料地保留了结合甲状腺激素的能力。在典型 TRα 突变体的晶体结构中可视化配体 T3 验证了这一观点。这一发现促使我们合成了不同的甲状腺激素类似物，确定了一种先导化合物 ES08，它比 T3 更有效地将共抑制物从突变型人 TRα 上解离。ES08 可挽救 RTHα 斑马鱼模型中的发育异常，并比 T3 更有效地诱导来自 RTHα 患者的含有 TRα 突变的细胞中的靶基因表达。我们的观察结果为开发合成配体提供了原理证明，这些配体可以缓解突变型 TRα-共抑制物复合物的转录抑制，从而治疗 RTHα。
