Please use this identifier to cite or link to this item: http://repositorio.unicamp.br/jspui/handle/REPOSIP/69130
Type: Artigo de periódico
Title: Identification of a New Hormone-Binding Site on the Surface of Thyroid Hormone Receptor
Author: Souza, PCT
Puhl, AC
Martinez, L
Aparicio, R
Nascimento, AS
Figueira, ACM
Nguyen, P
Webb, P
Skaf, MS
Polikarpov, I
Abstract: Thyroid 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.
Country: EUA
Editor: Endocrine Soc
Rights: embargo
Identifier DOI: 10.1210/me.2013-1359
Date Issue: 2014
Appears in Collections:Unicamp - Artigos e Outros Documentos

Files in This Item:
There are no files associated with this item.


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