ArticleThe Journal of clinical endocrinology and metabolism2019
Insight Into Molecular Determinants of T3 vs T4 Recognition From Mutations in Thyroid Hormone Receptor α and β.
Article in The Journal of clinical endocrinology and metabolism, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers, 1 of them a synthesis that pooled it.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
13 citing papers in PubMed, 1 synthesis or guideline pooled it, 25 citations in OpenAlex.
- 2024 European Thyroid Association Guidelines on diagnosis and management of genetic disorders of thyroid hormone transport, metabolism and action.European thyroid journal · 2024Guideline
- Asymmetric cross-reactivity of nuclear receptors reveals an evolutionary buffer between estrogen and androgen signaling.iScience · 2026Article
- Thyroid storm-induced cardiovascular complications and modalities of therapy: Up-to-date review.World journal of critical care medicine · 2025Review
- In silico development of RNA aptamer candidates against thyroid receptor.Journal of computer-aided molecular design · 2025Article
- Longevity, demographic characteristics, and socio-economic status are linked to triiodothyronine levels in the general population.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Intein-mediated thyroid hormone biosensors: towards controlled delivery of hormone therapy.Frontiers in systems biology · 2024Article
- Clinical and Biochemical Characteristics of Untreated Adult Patients With Resistance to Thyroid Hormone Alpha.Journal of the Endocrine Society · 2023Article
- MAFLD in Patients with Cushing's Disease Is Negatively Associated with Low Free Thyroxine Levels Rather than with Cortisol or TSH Levels.International journal of endocrinology · 2023Article
- Thyroid Hormone Abuse in Elite Sports: The Regulatory Challenge.The Journal of clinical endocrinology and metabolism · 2022Review
- Non-invasive Assay for Measurement of Fecal Triiodothyronine (T3) Metabolite Levels in European Mouflon (Frontiers in veterinary science · 2022Article
- FT3/FT4 ratio is correlated with all-cause mortality, cardiovascular mortality, and cardiovascular disease risk: NHANES 2007-2012.Frontiers in endocrinology · 2022Article
- Review
- The Clinical Spectrum of Resistance to Thyroid Hormone Alpha in Children and AdultsJournal of clinical research in pediatric endocrinology · 2021Review
Corrections and comments
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Authors and funding
7 authors at 3 institutions in 3 countries.
Funding
Abstract
contextThe two major forms of circulating thyroid hormones (THs) are T3 and T4. T3 is regarded as the biologically active hormone because it binds to TH receptors (TRs) with greater affinity than T4. However, it is currently unclear what structural mechanisms underlie this difference in affinity.
objectivePrompted by the identification of a novel M256T mutation in a resistance to TH (RTH)α patient, we investigated Met256 in TRα1 and the corresponding residue (Met310) in TRβ1, residues previously predicted by crystallographic studies in discrimination of T3 vs T4.
methodsClinical characterization of the RTHα patient and molecular studies (in silico protein modeling, radioligand binding, transactivation, and receptor-cofactor studies) were performed.
resultsStructural modeling of the TRα1-M256T mutant showed that distortion of the hydrophobic niche to accommodate the outer ring of ligand was more pronounced for T3 than T4, suggesting that this substitution has little impact on the affinity for T4. In agreement with the model, TRα1-M256T selectively reduced the affinity for T3. Also, unlike other naturally occurring TRα mutations, TRα1-M256T had a differential impact on T3- vs T4-dependent transcriptional activation. TRα1-M256A and TRβ1-M310T mutants exhibited similar discordance for T3 vs T4.
conclusionsMet256-TRα1/Met310-TRβ1 strongly potentiates the affinity of TRs for T3, thereby largely determining that T3 is the bioactive hormone rather than T4. These observations provide insight into the molecular basis for underlying the different affinity of TRs for T3 vs T4, delineating a fundamental principle of TH signaling.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.