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dc.contributor.authorBleicher, Lucas-
dc.contributor.authorAparicio, Ricardo-
dc.contributor.authorNunes, Fábio Macêdo-
dc.contributor.authorMartínez, Leandro-
dc.contributor.authorDias, Sandra Martha Gomes-
dc.contributor.authorFigueira, Ana Carolina Migliorini-
dc.contributor.authorSantos, Maria Auxiliadora Morim-
dc.contributor.authorVenturelli, Walter Hugo-
dc.contributor.authorSilva, Rosângela da-
dc.contributor.authorDonate, Paulo Marcos-
dc.contributor.authorNeves, Francisco de Assis Rocha-
dc.contributor.authorSimeoni, Luiz Alberto-
dc.contributor.authorBaxter, John Darling-
dc.contributor.authorWebb, Paul-
dc.contributor.authorSkaf, Munir Salomao-
dc.contributor.authorPolikarpov, Igor-
dc.date.accessioned2013-05-22T17:41:07Z-
dc.date.available2013-05-22T17:41:07Z-
dc.date.issued2008-
dc.identifier.citationBLEICHER, Lucas et al. Structural basis of GC-1 selectivity for thyroid hormone receptor isoforms. BMC Structural Biology, v. 8, n. 8, 2008. Disponível em: <http://www.biomedcentral.com/1472-6807/8/8>. Acesso em: 20 maio 2013. DOI: 10.1186/1472-6807-8-8.en
dc.identifier.urihttp://repositorio.unb.br/handle/10482/13179-
dc.description.abstractBackground: Thyroid receptors, TRα and TRβ, are involved in important physiological functions such as metabolism, cholesterol level and heart activities. Whereas metabolism increase and cholesterol level lowering could be achieved by TRβ isoform activation, TRα activation affects heart rates. Therefore, β-selective thyromimetics have been developed as promising drug-candidates for treatment of obesity and elevated cholesterol level. GC-1 [3,5-dimethyl-4-(4'-hydroxy-3'-isopropylbenzyl)-phenoxy acetic acid] has ability to lower LDL cholesterol with 600- to 1400-fold more potency and approximately two- to threefold more efficacy than atorvastatin (Lipitor©) in studies in rats, mice and monkeys. Results: To investigate GC-1 specificity, we solved crystal structures and performed molecular dynamics simulations of both isoforms complexed with GC-1. Crystal structures reveal that, in TRα Arg228 is observed in multiple conformations, an effect triggered by the differences in the interactions between GC-1 and Ser277 or the corresponding asparagine (Asn331) of TRβ. The corresponding Arg282 of TRβ is observed in only one single stable conformation, interacting effectively with the ligand. Molecular dynamics support this model: our simulations show that the multiple conformations can be observed for the Arg228 in TRα, in which the ligand interacts either strongly with the ligand or with the Ser277 residue. In contrast, a single stable Arg282 conformation is observed for TRβ, in which it strongly interacts with both GC-1 and the Asn331. Conclusion: Our analysis suggests that the key factors for GC-1 selectivity are the presence of an oxyacetic acid ester oxygen and the absence of the amino group relative to T3. These results shed light into the β-selectivity of GC-1 and may assist the development of new compounds with potential as drug candidates to the treatment of hypercholesterolemia and obesity.en
dc.language.isoInglêsen
dc.publisherBioMed Centralen
dc.rightsAcesso Abertoen
dc.titleStructural basis of GC-1 selectivity for thyroid hormone receptor isoformsen
dc.typeArtigoen
dc.subject.keywordTireóideen
dc.subject.keywordTireóide - hormôniosen
dc.subject.keywordReceptor do hormônio tireoideanoen
dc.rights.license© 2008 Bleicher et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Fonte: http://www.biomedcentral.com/1472-6807/8/8. Acesso em: 20 maio 2013.en
dc.identifier.doihttps://dx.doi.org/10.1186/1472-6807-8-8en
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