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|Type:||Artigo de periódico|
|Title:||On the Denaturation Mechanisms of the Ligand Binding Domain of Thyroid Hormone Receptors|
SOUZA, Paulo C. T.
BATISTA, Fernanda A. H.
PORTUGAL, Rodrigo V.
NASCIMENTO, Alessandro S.
LIMA, Luis M. T. R.
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 TR alpha and TR beta 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 TR alpha and TR beta 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 H 11, and the interaction of the region between H I and the Omega-loop with the core of the LBD, and (2) by shielding the hydrophobic H6 from hydration.|
|Editor:||AMER CHEMICAL SOC|
|Citation:||JOURNAL OF PHYSICAL CHEMISTRY B, v.114, n.3, p.1529-1540, 2010|
|Appears in Collections:||IQ - Artigos e Materiais de Revistas Científicas|
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|art_MARTINEZ_On_the_Denaturation_Mechanisms_of_the_Ligand_2010.pdf||published version||766.08 kB||Adobe PDF||View/Open|
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