Identification of a New Hormone-Binding Site on the Surface of Thyroid Hormone Receptor

dc.creatorSouza, PCT
dc.creatorPuhl, AC
dc.creatorMartinez, L
dc.creatorAparicio, R
dc.creatorNascimento, AS
dc.creatorFigueira, ACM
dc.creatorNguyen, P
dc.creatorWebb, P
dc.creatorSkaf, MS
dc.creatorPolikarpov, I
dc.date2014
dc.dateAPR
dc.date2014-07-30T18:00:16Z
dc.date2015-11-26T16:49:51Z
dc.date2014-07-30T18:00:16Z
dc.date2015-11-26T16:49:51Z
dc.date.accessioned2018-03-28T23:36:36Z
dc.date.available2018-03-28T23:36:36Z
dc.identifierMolecular Endocrinology. Endocrine Soc, v. 28, n. 4, n. 534, n. 545, 2014.
dc.identifier0888-8809
dc.identifierWOS:000335452100010
dc.identifier10.1210/me.2013-1359
dc.identifierhttp://www.repositorio.unicamp.br/jspui/handle/REPOSIP/69130
dc.identifierhttp://repositorio.unicamp.br/jspui/handle/REPOSIP/69130
dc.identifier.urihttp://repositorioslatinoamericanos.uchile.cl/handle/2250/1275571
dc.descriptionFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
dc.descriptionConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
dc.descriptionThyroid hormone receptors (TRs) are members of the nuclear receptor superfamily of ligand-activated transcription factors involved in cell differentiation, growth, and homeostasis. Although X-ray structures of many nuclear receptor ligand-binding domains (LBDs) reveal that the ligand binds within the hydrophobic core of the ligand-binding pocket, a few studies suggest the possibility of ligands binding to other sites. Here, we report a new x-ray crystallographic structure of TR-LBD that shows a second binding site for T-3 and T-4 located between H9, H10, and H11 of the TR alpha LBD surface. Statistical multiple sequence analysis, site-directed mutagenesis, and cell transactivation assays indicate that residues of the second binding site could be important for the TR function. We also conducted molecular dynamics simulations to investigate ligand mobility and ligand-protein interaction for T-3 and T-4 bound to this new TR surface-binding site. Extensive molecular dynamics simulations designed to compute ligand-protein dissociation constant indicate that the binding affinities to this surface site are of the order of the plasma and intracellular concentrations of the thyroid hormones, suggesting that ligands may bind to this new binding site under physiological conditions. Therefore, the second binding site could be useful as a new target site for drug design and could modulate selectively TR functions.
dc.descriptiono TEXTO COMPLETO DESTE ARTIGO, ESTARÁ DISPONÍVEL À PARTIR DE AGOSTO DE 2015.
dc.description28
dc.description4
dc.description534
dc.description545
dc.descriptionFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
dc.descriptionConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
dc.descriptionFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
dc.descriptionConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
dc.descriptionFAPESP [2010/17048-8, 2013/08293-7]
dc.languageen
dc.publisherEndocrine Soc
dc.publisherWashington
dc.publisherEUA
dc.relationMolecular Endocrinology
dc.relationMol. Endocrinol.
dc.rightsembargo
dc.sourceWeb of Science
dc.subjectMolecular-dynamics Simulations
dc.subjectVitamin-d-receptor
dc.subjectX-ray-diffraction
dc.subject3 Bf3 Site
dc.subjectLigand-binding
dc.subjectCoactivator-binding
dc.subjectEstrogen-receptor
dc.subjectAndrogen Receptor
dc.subjectInitial Configurations
dc.subjectAntiestrogen Action
dc.titleIdentification of a New Hormone-Binding Site on the Surface of Thyroid Hormone Receptor
dc.typeArtículos de revistas


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