Thyroxine-thyroid hormone receptor interactions

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Autor(es): dc.creatorSandler, Ben-
Autor(es): dc.creatorWebb, Paul-
Autor(es): dc.creatorApriletti, James W.-
Autor(es): dc.creatorHuber, B. Russell-
Autor(es): dc.creatorTogashi, Marie-
Autor(es): dc.creatorLima, Suzana T. Cunha-
Autor(es): dc.creatorJuric, Sanja-
Autor(es): dc.creatorNilsson, Stefan-
Autor(es): dc.creatorWagner, Richard-
Autor(es): dc.creatorFletterick, Robert J.-
Autor(es): dc.creatorBaxter, John Darling-
Data de aceite: dc.date.accessioned2021-10-14T18:20:37Z-
Data de disponibilização: dc.date.available2021-10-14T18:20:37Z-
Data de envio: dc.date.issued2013-06-04-
Data de envio: dc.date.issued2013-06-04-
Data de envio: dc.date.issued2004-
Fonte completa do material: dc.identifierhttp://repositorio.unb.br/handle/10482/13249-
Fonte completa do material: dc.identifierhttps://dx.doi.org/10.1074/jbc.M410124200-
Fonte: dc.identifier.urihttp://educapes.capes.gov.br/handle/capes/629333-
Descrição: dc.descriptionABSTRACT-
Descrição: dc.descriptionThyroid hormone (TH) actions are mediated by nuclear receptors (TRs α and β) that bind triiodothyronine (T3, 3,5,3′-triiodo-l-thyronine) with high affinity, and its precursor thyroxine (T4, 3,5,3′,5′-tetraiodo-l-thyronine) with lower affinity. T4 contains a bulky 5′ iodine group absent from T3. Because T3 is buried in the core of the ligand binding domain (LBD), we have predicted that TH analogues with 5′ substituents should fit poorly into the ligand binding pocket and perhaps behave as antagonists. We therefore examined how T4 affects TR activity and conformation. We obtained several lines of evidence (ligand dissociation kinetics, migration on hydrophobic interaction columns, and non-denaturing gels) that TR-T4 complexes adopt a conformation that differs from TR-T3 complexes in solution. Nonetheless, T4 behaves as an agonist in vitro (in effects on coregulator and DNA binding) and in cells, when conversion to T3 does not contribute to agonist activity. We determined x-ray crystal structures of the TRβ LBD in complex with T3 and T4 at 2.5-Å and 3.1-Å resolution. Comparison of the structures reveals that TRβ accommodates T4 through subtle alterations in the loop connecting helices 11 and 12 and amino acid side chains in the pocket, which, together, enlarge a niche that permits helix 12 to pack over the 5′ iodine and complete the coactivator binding surface. While T3 is the major active TH, our results suggest that T4 could activate nuclear TRs at appropriate concentrations. The ability of TR to adapt to the 5′ extension should be considered in TR ligand design.-
Formato: dc.formatapplication/pdf-
Publicador: dc.publisherThe American Society for Biochemistry and Molecular Biology, Inc.-
Direitos: dc.rightsAcesso Aberto-
Direitos: dc.rightsThe Journal of Biological Chemistry - Authors need NOT contact the journal to obtain rights to reuse their own material. They are automatically granted permission to do the following: Reproduce an article for use in the author's courses. (If the author is employed by an academic institution, that institution also may reproduce the article for teaching purposes.). Fonte: http://www.jbc.org/site/misc/Copyright_Permission.xhtml. Acesso em: 20 maio 2013.-
Palavras-chave: dc.subjectTireóide - hormônios-
Palavras-chave: dc.subjectTiroxina-
Palavras-chave: dc.subjectReceptor do hormônio tireoideano-
Título: dc.titleThyroxine-thyroid hormone receptor interactions-
Tipo de arquivo: dc.typelivro digital-
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