Please use this identifier to cite or link to this item: http://repositorio.unicamp.br/jspui/handle/REPOSIP/214
Full metadata record
DC FieldValueLanguage
dc.contributor.CRUESPUNIVERSIDADE ESTADUAL DE CAMPINASpt_BR
dc.subject.otherMOLECULAR-DYNAMICS SIMULATIONSen
dc.subject.otherX-RAY-DIFFRACTIONen
dc.subject.otherAGONIST GC-1en
dc.subject.otherLIGAND DISSOCIATIONen
dc.subject.otherGENE SUPERFAMILYen
dc.subject.otherSERUM-LIPIDSen
dc.subject.otherTR-BETAen
dc.subject.otherCHOLESTEROLen
dc.subject.otherMICEen
dc.subject.otherTRIIODOTHYRONINEen
dc.typeArtigo de periódicopt_BR
dc.type.categoryoriginal articlept_BR
dc.type.versionpublishedVersionpt_BR
dc.titleStructural basis of GC-1 selectivity for thyroid hormone receptor isoformspt_BR
dc.contributor.authorBLEICHER, Lucaspt_BR
dc.contributor.authorAPARICIO, Ricardopt_BR
dc.contributor.authorNUNES, Fabio M.pt_BR
dc.contributor.authorMARTINEZ, Leandropt_BR
dc.contributor.authorDIAS, Sandra M. Gomespt_BR
dc.contributor.authorFIGUEIRA, Ana Carolina Migliorinipt_BR
dc.contributor.authorSANTOS, Maria Auxiliadora Morimpt_BR
dc.contributor.authorVENTURELLI, Walter H.pt_BR
dc.contributor.authorSILVA, Rosangela dapt_BR
dc.contributor.authorDONATE, Paulo Marcospt_BR
dc.contributor.authorNEVES, Francisco A. R.pt_BR
dc.contributor.authorSIMEONI, Luiz A.pt_BR
dc.contributor.authorBAXTER, John D.pt_BR
dc.contributor.authorWEBB, Paulpt_BR
dc.contributor.authorSKAF, Munir S.pt_BR
dc.contributor.authorPOLIKARPOV, Igorpt_BR
unicamp.authorAPARICIO, Ricardo:Universidade Estadual de Campinas, Instituto de Químicapt_BR
unicamp.authorMARTINEZ, Leandro:Universidade Estadual de Campinas, Instituto de Químicapt_BR
unicamp.authorSKAF, Munir S.:Universidade Estadual de Campinas, Instituto de Químicapt_BR
unicamp.author.externalDIAS, Sandra M. Gomespt
unicamp.author.externalSILVA, Rosangela dapt
unicamp.author.externalNEVES, Francisco A. R.pt
unicamp.author.externalSIMEONI, Luiz A.pt
unicamp.author.externalBAXTER, John D.pt
unicamp.author.externalWEBB, Paulpt
unicamp.author.externalBLEICHER, Lucaspt
unicamp.author.externalNUNES, Fabio M.pt
unicamp.author.externalFIGUEIRA, Ana Carolina Migliorinipt
unicamp.author.externalSANTOS, Maria Auxiliadora Morimpt
unicamp.author.externalVENTURELLI, Walter H.pt
unicamp.author.externalDONATE, Paulo Mpt
dc.subject.wosBiophysicspt_BR
dc.description.abstractBackground: Thyroid receptors, TRa and TR beta, 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 TR beta isoform activation, TRa activation affects heart rates. Therefore, beta-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(C)) 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 TRa 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 TR beta. The corresponding Arg282 of TR beta 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 TR alpha, 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 TR beta, 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 T(3). These results shed light into the beta-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.relation.ispartofBMC Structural Biologypt_BR
dc.publisher.countryInglaterrapt_BR
dc.publisherBIOMED CENTRAL LTDpt_BR
dc.date.issued2008pt_BR
dc.identifier.citationBMC STRUCTURAL BIOLOGY, v.8, 2008pt_BR
dc.language.isoengpt_BR
dc.description.volume8pt_BR
dc.rightsabertopt_BR
dc.rights.holderCopyright BIOMED CENTRAL LTDpt_BR
dc.sourceWOSpt_BR
unicamp.cruespUSPpt_BR
dc.identifier.issn1471-2237pt_BR
dc.identifier.doi10.1186/1472-6807-8-8pt_BR
dc.identifier.urlhttp://dx.doi.org/10.1186/1472-6807-8-8pt_BR
dc.identifier.urlhttp://apps.isiknowledge.com/InboundService.do?Func=Frame&product=WOS&action=retrieve&SrcApp=EndNote&UT=000254549600003&Init=Yes&SrcAuth=ResearchSoft&mode=FullRecordpt_BR
dc.date.available2013-07-26T17:56:24Z
dc.date.available2016-07-01T12:54:05Z-
dc.date.accessioned2013-07-26T17:56:24Z
dc.date.accessioned2016-07-01T12:54:05Z-
dc.description.provenanceMade available in DSpace on 2013-07-26T17:56:24Z (GMT). No. of bitstreams: 2 art_BLEICHER_Structural_basis_of_GC-1_selectivity_for_thyroid_2008.pdf: 851213 bytes, checksum: 93c9965c0cff0aa87bd6c36f371f43c0 (MD5) art_BLEICHER_Structural_basis_of_GC-1_selectivity_for_thyroid_2008.pdf.txt: 58726 bytes, checksum: 40770ab7b710a24520c4fd5b12382639 (MD5) Previous issue date: 2008en
dc.description.provenanceMade available in DSpace on 2016-07-01T12:54:05Z (GMT). No. of bitstreams: 2 art_BLEICHER_Structural_basis_of_GC-1_selectivity_for_thyroid_2008.pdf: 851213 bytes, checksum: 93c9965c0cff0aa87bd6c36f371f43c0 (MD5) art_BLEICHER_Structural_basis_of_GC-1_selectivity_for_thyroid_2008.pdf.txt: 58726 bytes, checksum: 40770ab7b710a24520c4fd5b12382639 (MD5) Previous issue date: 2008en
dc.identifier.urihttp://www.repositorio.unicamp.br/jspui/handle/REPOSIP/214
dc.identifier.urihttp://repositorio.unicamp.br/jspui/handle/REPOSIP/214-
dc.contributor.unidadeIQpt
Appears in Collections:IQ - Artigos e Outros Documentos

Files in This Item:
File Description SizeFormat 
art_BLEICHER_Structural_basis_of_GC-1_selectivity_for_thyroid_2008.pdfpublished version831.26 kBAdobe PDFView/Open


Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.