7QDT

Crystal structure of a mutant (P393GX) Thyroid Receptor Alpha ligand binding domain designed to model dominant negative human mutations.

7QDT の概要

• エントリーDOI: 10.2210/pdb7qdt/pdb
• 分子名称: Isoform Alpha-1 of Thyroid hormone receptor alpha, 3,5,3'TRIIODOTHYRONINE (3 entities in total)
• 機能のキーワード: nuclear receptor, thyroid hormone, mutation, nuclear protein
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 27376.87

構造登録者

Romartinez-Alonso, B.,Fairall, L.,Agostini, M.,Chatterjee, K.,Schwabe, J. (登録日: 2021-11-30, 公開日: 2022-01-26, 最終更新日: 2024-01-31)

主引用文献

Romartinez-Alonso, B.,Agostini, M.,Jones, H.,McLellan, J.,Sood, D.E.,Tomkinson, N.,Marelli, F.,Gentile, I.,Visser, W.E.,Schoenmakers, E.,Fairall, L.,Privalsky, M.,Moran, C.,Persani, L.,Chatterjee, K.,Schwabe, J.W.R.
Structure-Guided Approach to Relieving Transcriptional Repression in Resistance to Thyroid Hormone alpha.
Mol.Cell.Biol., 42:e0036321-e0036321, 2022

PubMed 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.

PubMed: 34871063
DOI: 10.1128/MCB.00363-21

実験手法

X-RAY DIFFRACTION (3 Å)