Please use this identifier to cite or link to this item: http://repositorio.unicamp.br/jspui/handle/REPOSIP/201151
Type: Artigo de periódico
Title: Identification Of A New Hormone-binding Site On The Surface Of Thyroid Hormone Receptor.
Author: Souza, P C T
Puhl, A C
Martínez, L
Aparício, R
Nascimento, A S
Figueira, A C M
Nguyen, P
Webb, P
Skaf, M S
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 T3 and T4 located between H9, H10, and H11 of the TRα 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 T3 and T4 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.
Subject: Amino Acids
Binding Sites
Cell Line
Crystallography, X-ray
Humans
Ligands
Molecular Dynamics Simulation
Protein Structure, Tertiary
Receptors, Thyroid Hormone
Structure-activity Relationship
Thyroid Hormones
Transcriptional Activation
Citation: Molecular Endocrinology (baltimore, Md.). v. 28, n. 4, p. 534-45, 2014-Apr.
Rights: fechado
Identifier DOI: 10.1210/me.2013-1359
Address: http://www.ncbi.nlm.nih.gov/pubmed/24552590
Date Issue: 2014
Appears in Collections:Unicamp - Artigos e Outros Documentos

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