Please use this identifier to cite or link to this item:
Type: Artigo de periódico
Title: On The Denaturation Mechanisms Of The Ligand Binding Domain Of Thyroid Hormone Receptors.
Author: Martínez, Leandro
Souza, Paulo C T
Garcia, Wanius
Batista, Fernanda A H
Portugal, Rodrigo V
Nascimento, Alessandro S
Nakahira, Marcel
Lima, Luis M T R
Polikarpov, Igor
Skaf, Munir S
Abstract: The ligand binding domain (LBD) of nuclear hormone receptors adopts a very compact, mostly alpha-helical structure that binds specific ligands with very high affinity. We use circular dichroism spectroscopy and high-temperature molecular dynamics simulations to investigate unfolding of the LBDs of thyroid hormone receptors (TRs). A molecular description of the denaturation mechanisms is obtained by molecular dynamics simulations of the TRalpha and TRbeta LBDs in the absence and in the presence of the natural ligand Triac. The simulations show that the thermal unfolding of the LBD starts with the loss of native contacts and secondary structure elements, while the structure remains essentially compact, resembling a molten globule state. This differs from most protein denaturation simulations reported to date and suggests that the folding mechanism may start with the hydrophobic collapse of the TR LBDs. Our results reveal that the stabilities of the LBDs of the TRalpha and TRbeta subtypes are affected to different degrees by the binding of the isoform selective ligand Triac and that ligand binding confers protection against thermal denaturation and unfolding in a subtype specific manner. Our simulations indicate two mechanisms by which the ligand stabilizes the LBD: (1) by enhancing the interactions between H8 and H11, and the interaction of the region between H1 and the Omega-loop with the core of the LBD, and (2) by shielding the hydrophobic H6 from hydration.
Subject: Amino Acid Sequence
Circular Dichroism
Hydrophobic And Hydrophilic Interactions
Molecular Dynamics Simulation
Molecular Sequence Data
Protein Denaturation
Protein Folding
Protein Stability
Protein Structure, Secondary
Protein Structure, Tertiary
Sequence Alignment
Substrate Specificity
Thyroid Hormone Receptors Alpha
Thyroid Hormone Receptors Beta
Citation: The Journal Of Physical Chemistry. B. v. 114, n. 3, p. 1529-40, 2010-Jan.
Rights: fechado
Identifier DOI: 10.1021/jp911554p
Date Issue: 2010
Appears in Collections:Unicamp - Artigos e Outros Documentos

Files in This Item:
File SizeFormat 
pmed_20043653.pdf6.46 MBAdobe PDFView/Open

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