{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T20:45:27Z","timestamp":1792010727106,"version":"4.4.0"},"reference-count":30,"publisher":"The Endocrine Society","issue":"8","license":[{"start":{"date-parts":[[2019,3,1]],"date-time":"2019-03-01T00:00:00Z","timestamp":1551398400000},"content-version":"vor","delay-in-days":1,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Zon-MWTOP","award":["91212044"],"award-info":[{"award-number":["91212044"]}]},{"DOI":"10.13039\/501100002842","name":"Chiang Mai University","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002842","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004440","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["210755\/Z\/18\/Z"],"award-info":[{"award-number":["210755\/Z\/18\/Z"]}],"id":[{"id":"10.13039\/100004440","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Erasmus MC Medical Research Advisory Committee (MRACE) grant"},{"name":"NIHR Cambridge Biomedical Centre"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,8,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Context<\/jats:title>\n                    <jats:p>The 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Prompted by the identification of a novel M256T mutation in a resistance to TH (RTH)\u03b1 patient, we investigated Met256 in TR\u03b11 and the corresponding residue (Met310) in TR\u03b21, residues previously predicted by crystallographic studies in discrimination of T3 vs T4.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Clinical characterization of the RTH\u03b1 patient and molecular studies (in silico protein modeling, radioligand binding, transactivation, and receptor\u2013cofactor studies) were performed.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Structural modeling of the TR\u03b11-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, TR\u03b11-M256T selectively reduced the affinity for T3. Also, unlike other naturally occurring TR\u03b1 mutations, TR\u03b11-M256T had a differential impact on T3- vs T4-dependent transcriptional activation. TR\u03b11-M256A and TR\u03b21-M310T mutants exhibited similar discordance for T3 vs T4.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Met256-TR\u03b11\/Met310-TR\u03b21 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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1210\/jc.2018-02794","type":"journal-article","created":{"date-parts":[[2019,2,28]],"date-time":"2019-02-28T15:19:23Z","timestamp":1551367163000},"page":"3491-3500","source":"Crossref","is-referenced-by-count":28,"title":["Insight Into Molecular Determinants of T3 vs T4 Recognition From Mutations in Thyroid Hormone Receptor \u03b1 and \u03b2"],"prefix":"10.1210","volume":"104","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3277-994X","authenticated-orcid":false,"given":"Karn","family":"Wejaphikul","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, Erasmus Medical Center, Academic Center for Thyroid Diseases, Rotterdam, Netherlands"},{"name":"Department of Pediatrics, Faculty of Medicine, Chiang Mai University, Chiang Mai, 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