7QDT
Crystal structure of a mutant (P393GX) Thyroid Receptor Alpha ligand binding domain designed to model dominant negative human mutations.
Summary for 7QDT
| Entry DOI | 10.2210/pdb7qdt/pdb |
| Descriptor | Isoform Alpha-1 of Thyroid hormone receptor alpha, 3,5,3'TRIIODOTHYRONINE (3 entities in total) |
| Functional Keywords | nuclear receptor, thyroid hormone, mutation, nuclear protein |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 27376.87 |
| Authors | Romartinez-Alonso, B.,Fairall, L.,Agostini, M.,Chatterjee, K.,Schwabe, J. (deposition date: 2021-11-30, release date: 2022-01-26, Last modification date: 2024-01-31) |
| Primary citation | 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 Cited by 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: 34871063DOI: 10.1128/MCB.00363-21 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (3 Å) |
Structure validation
Download full validation report
