Helix 12 Dynamics and Thyroid Hormone Receptor Activity: Experimental and Molecular Dynamics Studies of Ile280 Mutants

dc.creatorSouza, PCT
dc.creatorBarra, GB
dc.creatorVelasco, LFR
dc.creatorRibeiro, ICJ
dc.creatorSimeoni, LA
dc.creatorTogashi, M
dc.creatorWebb, P
dc.creatorNeves, FAR
dc.creatorSkaf, MS
dc.creatorMartinez, L
dc.creatorPolikarpov, I
dc.date2011
dc.dateOCT 7
dc.date2014-07-30T17:49:39Z
dc.date2015-11-26T16:32:14Z
dc.date2014-07-30T17:49:39Z
dc.date2015-11-26T16:32:14Z
dc.date.accessioned2018-03-28T23:13:35Z
dc.date.available2018-03-28T23:13:35Z
dc.identifierJournal Of Molecular Biology. Academic Press Ltd- Elsevier Science Ltd, v. 412, n. 5, n. 882, n. 893, 2011.
dc.identifier0022-2836
dc.identifierWOS:000295949800011
dc.identifier10.1016/j.jmb.2011.04.014
dc.identifierhttp://www.repositorio.unicamp.br/jspui/handle/REPOSIP/68220
dc.identifierhttp://repositorio.unicamp.br/jspui/handle/REPOSIP/68220
dc.identifier.urihttp://repositorioslatinoamericanos.uchile.cl/handle/2250/1270447
dc.descriptionFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
dc.descriptionConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
dc.descriptionCoordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
dc.descriptionNuclear hormone receptors (NRs) form a family of transcription factors that mediate cellular responses initiated by hormone binding. It is generally recognized that the structure and dynamics of the C-terminal helix 12 (H12) of NRs' ligand binding domain (LBD) are fundamental to the recognition of coactivators and corepressors that modulate receptor function. Here we study the role of three mutations in the I280 residue of H12 of thyroid hormone receptors using site-directed mutagenesis, functional assays, and molecular dynamics simulations. Although residues at position 280 do not interact with coactivators or with the ligand, we show that its mutations can selectively block coactivator and corepressor binding, and affect hormone binding affinity differently. Molecular dynamics simulations suggest that ligand affinity is reduced by indirectly displacing the ligand in the binding pocket, facilitating water penetration and ligand destabilization. Mutations I280R and I280K link H12 to the LBD by forming salt bridges with E457 in H12, stabilizing H12 in a conformation that blocks both corepressor and coactivator recruitment. The I280M mutation, in turn, blocks corepressor binding, but appears to enhance coactivator affinity, suggesting stabilization of H12 in agonist conformation. (C) 2011 Elsevier Ltd. All rights reserved.
dc.description412
dc.description5
dc.descriptionSI
dc.description882
dc.description893
dc.descriptionFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
dc.descriptionConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
dc.descriptionCoordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
dc.descriptionFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
dc.descriptionConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
dc.descriptionCoordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
dc.descriptionCNPq [476895/2008-1, 620195/2008]
dc.languageen
dc.publisherAcademic Press Ltd- Elsevier Science Ltd
dc.publisherLondon
dc.publisherInglaterra
dc.relationJournal Of Molecular Biology
dc.relationJ. Mol. Biol.
dc.rightsfechado
dc.rightshttp://www.elsevier.com/about/open-access/open-access-policies/article-posting-policy
dc.sourceWeb of Science
dc.subjectnuclear hormone receptor
dc.subjectthyroid
dc.subjectcofactor recruitment
dc.subjectmolecular dynamics simulations
dc.subjectLigand-binding Domain
dc.subjectRetinoic-acid
dc.subjectEstrogen-receptor
dc.subjectNuclear Receptors
dc.subjectCrystal-structure
dc.subjectRxr-alpha
dc.subjectInitial Configurations
dc.subjectConformational-changes
dc.subjectCorepressor Binding
dc.subjectMass-spectrometry
dc.titleHelix 12 Dynamics and Thyroid Hormone Receptor Activity: Experimental and Molecular Dynamics Studies of Ile280 Mutants
dc.typeArtículos de revistas


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