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dc.contributor.authorRomartinez-Alonso, Beatriz
dc.contributor.authorAgostini, Maura
dc.contributor.authorJones, Heulyn
dc.contributor.authorMcLellan, Jayde
dc.contributor.authorSood, D Eilidh
dc.contributor.authorTomkinson, Nicholas
dc.contributor.authorMarelli, Federica
dc.contributor.authorGentile, Ilaria
dc.contributor.authorVisser, W Edward
dc.contributor.authorSchoenmakers, Erik
dc.contributor.authorFairall, Louise
dc.contributor.authorPrivalsky, Martin
dc.contributor.authorMoran, Carla
dc.contributor.authorPersani, Luca
dc.contributor.authorChatterjee, Krishna
dc.contributor.authorSchwabe, John WR
dc.description.abstractMutations 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.
dc.description.sponsorshipNIHR Cambridge Biomedical Research Centre
dc.publisherAmerican Society for Microbiology
dc.rightsAttribution 4.0 International
dc.titleStructure-Guided Approach to Relieving Transcriptional Repression in Resistance to Thyroid Hormone α.
dc.publisher.departmentDepartment of Clinical Biochemistry
prism.publicationNameMol Cell Biol
dc.contributor.orcidSchoenmakers, Erik [0000-0003-0674-8282]
dc.contributor.orcidPersani, Luca [0000-0003-2068-9581]
dc.contributor.orcidChatterjee, Krishna [0000-0002-2654-8854]
dc.contributor.orcidSchwabe, John WR [0000-0003-2865-4383]
rioxxterms.typeJournal Article/Review
pubs.funder-project-idWellcome Trust (095564/Z/11/Z)
pubs.funder-project-idMedical Research Council (MC_UU_12012/5)
pubs.funder-project-idWellcome Trust (210755/Z/18/Z)
pubs.licence-display-nameApollo Repository Deposit Licence Agreement

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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International