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dc.contributor.CRUESPUNIVERSIDADE ESTADUAL DE CAMPINASpt_BR
dc.subject.otherTIME-DEPENDENT HARTREEen
dc.subject.otherTHYROID-HORMONE RECEPTORSen
dc.subject.otherRETINOIC ACID RECEPTORen
dc.subject.otherBINDING DOMAINen
dc.subject.otherMULTIFUNCTIONAL MEDICINESen
dc.subject.otherCONFORMATIONAL-CHANGESen
dc.subject.otherFORCE-FIELDen
dc.subject.otherF-DOMAINen
dc.subject.otherMYOGLOBINen
dc.subject.otherANTIESTROGENSen
dc.typeArtigo de periódicopt_BR
dc.type.categoryoriginal articlept_BR
dc.type.versionpublishedVersionpt_BR
dc.titleLigand dissociation from estrogen receptor is mediated by receptor dimerization: Evidence from molecular dynamics simulationspt_BR
dc.contributor.authorSONODA, Milton T.pt_BR
dc.contributor.authorMARTINEZ, Leandropt_BR
dc.contributor.authorWEBB, Paulpt_BR
dc.contributor.authorSKAF, Munir S.pt_BR
dc.contributor.authorPOLIKARPOV, Igorpt_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.externalSONODA, Milton T.pt
unicamp.author.externalWEBB, Paulpt
unicamp.author.externalPOLIKARPOV, Igorpt
dc.subject.wosEndocrinology & Metabolismpt_BR
dc.description.abstractEstrogen Receptor (ER) is an important target for pharmaceutical design. Like other ligand-dependent transcription factors, hormone binding regulates ER transcriptional activity. Nevertheless, the mechanisms by which ligands enter and leave ERs and other nuclear receptors remain poorly understood. Here, we report results of locally enhanced sampling molecular dynamics simulations to identify dissociation pathways of two ER ligands [the natural hormone 17 beta-estradiol (E-2) and the selective ER modulator raloxifene (RAL)] from the human ER alpha ligand-binding domain in monomeric and dimeric forms. E-2 dissociation occurs via three different pathways in ER monomers. One resembles the mousetrap mechanism (Path I), involving repositioning of helix 12 (H12), others involve the separation of H8 and H11 (Path II), and a variant of this pathway at the bottom of the ligand-binding domain (Path II`). RAL leaves the receptor through Path I and a Path I variant in which the ligand leaves the receptor through the loop region between H11 and H12 (Path I`). Remarkably, ER dimerization strongly suppresses Paths II and II` for E-2 dissociation and modifies RAL escape routes. We propose that differences in ligand release pathways detected in the simulations for ER monomers and dimers provide an explanation for previously observed effects of ER quaternary state on ligand dissociation rates and suggest that dimerization may play an important, and hitherto unexpected, role in regulation of ligand dissociation rates throughout the nuclear receptor family.en
dc.relation.ispartofMolecular Endocrinologypt_BR
dc.publisher.countryEstados Unidospt_BR
dc.publisherENDOCRINE SOCpt_BR
dc.date.issued2008pt_BR
dc.identifier.citationMOLECULAR ENDOCRINOLOGY, v.22, n.7, p.1565-1578, 2008pt_BR
dc.language.isoengpt_BR
dc.description.volume22pt_BR
dc.description.issuenumber7pt_BR
dc.description.firstpage1565pt_BR
dc.description.lastpage1578pt_BR
dc.rightsfechadopt_BR
dc.rights.holderCopyright ENDOCRINE SOCpt_BR
dc.sourceWOSpt_BR
unicamp.cruespUSPpt_BR
dc.identifier.issn0888-8809pt_BR
dc.identifier.doi10.1210/me.2007-0501pt_BR
dc.identifier.urlhttp://apps.isiknowledge.com/InboundService.do?Func=Frame&product=WOS&action=retrieve&SrcApp=EndNote&UT=000257144500005&Init=Yes&SrcAuth=ResearchSoft&mode=FullRecordpt_BR
dc.identifier.urlhttp://dx.doi.org/10.1210/me.2007-0501pt_BR
dc.date.available2013-07-26T17:59:23Z
dc.date.available2016-07-01T12:54:11Z-
dc.date.accessioned2013-07-26T17:59:23Z
dc.date.accessioned2016-07-01T12:54:11Z-
dc.description.provenanceMade available in DSpace on 2013-07-26T17:59:23Z (GMT). No. of bitstreams: 2 art_SONODA_Ligand_dissociation_from_estrogen_receptor_is_mediated_2008.pdf.txt: 64595 bytes, checksum: 6239b1bdd1eb0e50848073f84c01492d (MD5) art_SONODA_Ligand_dissociation_from_estrogen_receptor_is_mediated_2008.pdf: 716019 bytes, checksum: 21763f7fbadc55cea5b6983a1513a9da (MD5) Previous issue date: 2008en
dc.description.provenanceMade available in DSpace on 2016-07-01T12:54:11Z (GMT). No. of bitstreams: 2 art_SONODA_Ligand_dissociation_from_estrogen_receptor_is_mediated_2008.pdf.txt: 64595 bytes, checksum: 6239b1bdd1eb0e50848073f84c01492d (MD5) art_SONODA_Ligand_dissociation_from_estrogen_receptor_is_mediated_2008.pdf: 716019 bytes, checksum: 21763f7fbadc55cea5b6983a1513a9da (MD5) Previous issue date: 2008en
dc.identifier.urihttp://www.repositorio.unicamp.br/jspui/handle/REPOSIP/1043
dc.identifier.urihttp://repositorio.unicamp.br/jspui/handle/REPOSIP/1043-
dc.contributor.unidadeIQpt
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