TITLE

Structural basis of GC-1 selectivity for thyroid hormone receptor isoforms

AUTHOR(S)
Bleicher, Lucas; Aparicio, Ricardo; Nunes, Fabio M.; Martinez, Leandro; Gomes Dias, Sandra M.; Figueira, Ana Carolina Migliorini; Santos, Maria Auxiliadora Morim; Venturelli, Walter H.; Da Silva, Rosangela; Donate, Paulo Marcos; Neves, Francisco A. R.; Simeoni, Luiz A.; Baxter, John D.; Webb, Paul; Skaf, Munir S.; Polikarpov, Igor
PUB. DATE
January 2008
SOURCE
BMC Structural Biology;2008, Vol. 8, Special section p1
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
ABSTRACT
Background: Thyroid receptors, TRα and TRβ, are involved in important physiological functions such as metabolism, cholesterol level and heart activities. Whereas metabolism increase and cholesterol level lowering could be achieved by TRβ isoform activation, TRα activation affects heart rates. Therefore, β-selective thyromimetics have been developed as promising drug-candidates for treatment of obesity and elevated cholesterol level. GC-1 [3,5-dimethyl-4-(4'- hydroxy-3'-isopropylbenzyl)-phenoxy acetic acid] has ability to lower LDL cholesterol with 600- to 1400-fold more potency and approximately two- to threefold more efficacy than atorvastatin (Lipitor©) in studies in rats, mice and monkeys. Results: To investigate GC-1 specificity, we solved crystal structures and performed molecular dynamics simulations of both isoforms complexed with GC-1. Crystal structures reveal that, in TRα Arg228 is observed in multiple conformations, an effect triggered by the differences in the interactions between GC-1 and Ser277 or the corresponding asparagine (Asn331) of TRβ. The corresponding Arg282 of TRβ is observed in only one single stable conformation, interacting effectively with the ligand. Molecular dynamics support this model: our simulations show that the multiple conformations can be observed for the Arg228 in TRα, in which the ligand interacts either strongly with the ligand or with the Ser277 residue. In contrast, a single stable Arg282 conformation is observed for TRβ, in which it strongly interacts with both GC-1 and the Asn331. Conclusion: Our analysis suggests that the key factors for GC-1 selectivity are the presence of an oxyacetic acid ester oxygen and the absence of the amino group relative to T3. These results shed light into the β-selectivity of GC-1 and may assist the development of new compounds with potential as drug candidates to the treatment of hypercholesterolemia and obesity.
ACCESSION #
35702913

 

Related Articles

  • Thyroid hormone: multiple effects on cholesterol synthesis and metabolism. Kalvaitis, Katie; Klein, Irwin L. // Cardiology Today;Jun2008, Vol. 11 Issue 6, p43 

    The article reports that treatment with thyroid hormone has multiple effects on cholesterol synthesis and metabolism, according to Elizabeth N. Pearce, assistant professor of medicine, section of endocrinology, diabetes and nutrition, Boston University School of Medicine in Massachusetts. Pearce...

  • Cardiovascular disease: Hormone mimic reduces cholesterol. Crunkhorn, Sarah // Nature Reviews Drug Discovery;Mar2008, Vol. 7 Issue 3, p203 

    The article discusses the study "The thyroid hormone mimetic compound KB2115 lower plasma LDL cholesterol and simulates bile acid synthesis without cardiac effects in humans," by Baxter and colleagues. The researchers presented the first clinical data for KB2115 (epirome), a novel mimetic of...

  • Dose and time-dependent hypercholesterolemic effects of iodine excess via TRβ1-mediated down regulation of hepatic LDLr gene expression. Li -Na Zhao; Jian Xu; Xiao-Lin Peng; Li-Yue Tian; Li-Ping Hao; Xue-Feng Yang; Chen-Jiang Ying; Xiu-Fa Sun // European Journal of Nutrition;Aug2010, Vol. 49 Issue 5, p257 

    With the global improvement of iodine nutrition, iodine excess is emerging as a new concern. The aim of this study is to illustrate the physiological effects and potential molecular mechanisms of excessive iodine intake on lipid metabolism. Balb/c mice were given drinking water containing...

  • Sobetirome: A Selective Thyromimetic for the Treatment of Dyslipidemia. Tancevski, Ivan; Demetz, Egon; Eller, Philipp // Recent Patents on Cardiovascular Drug Discovery;Jan2011, Vol. 6 Issue 1, p16 

    Atherosclerosis and its clinical sequelae still represent the primary cause of death in Western societies. During the past 25 years, a novel drug class to treat dyslipidemia, a main risk factor for coronary artery disease, emerged: liverand thyroid hormone receptor isoform �- selective...

  • Serum Concentrations of Lipids and Lipoproteins and Their Correlations together and with Thyroid Hormones in Iranian Water Buffalo (Bulbalus bulbalis). Tajik, Javad; Nazifi, Saeed // Asian Journal of Animal Sciences;2011, Vol. 5 Issue 3, p196 

    No abstract available.

  • Increased Atherogenic Low-Density Lipoprotein Cholesterol in Untreated Subclinical Hypothyroidism. George Mikhail; Sameer Alshammari; Mohammed Alenezi; Maged Mansour; Nesreen Khalil // Endocrine Practice;Jul2008, Vol. 14 Issue 5, p570 

    Objective: To evaluate the effects of physiologic doses of levothyroxine replacement on the lipoprotein profile in patients with subclinical hypothyroidism (SCH).Methods: In a prospective, double-blind, placebo-controlled study, we enrolled 120 patients—mostly, but not exclusively,...

  • A CORRELATION STUDY BETWEEN SERUM ZINC AND PLASMA TOTAL CHOLESTEROL, HIGH DENSITY AND LOW DENSITY LIPOPROTEIN CHOLESTEROL IN THYROID DYSFUNCTION. Maradi, Ravindra; Joshi, Vivek R.; Mallick, Ayaz Khurram; Reddy, Gummadi Maheshwar; Shorey, Gaurav; Tey, Raghavendra Vikram // International Journal of Pharmaceutical Sciences Review & Resear;Mar/Apr2011, Vol. 7 Issue 2, p122 

    Diseases of thyroid gland can affect nearly every function of our body. Thyroid hormone binding transcription factors, which are essential for modulation of gene expression, contain zinc bound to cysteine residues and also thyroid hormones influence zinc metabolism by affecting zinc absorption...

  • Thyroid function and metabolic syndrome. Agarwal, Pankaj; Singh, Mohit Mohan; Gutch, Manish // Thyroid Research & Practice;Sep-Dec2015, Vol. 12 Issue 3, p85 

    The authors present insights on thyroid function and metabolic syndrome in light of the rising prevalence of obesity in India. Topics discussed include the effect of obesity on thyroid hormones, the effect of thyroid hormones on low density lipoprotein cholesterol (LDL-C), and thyroid disorders...

  • Thyroid hormone analogue for dyslipidemia. Kuritzky, Louis // Clinical Cardiology Alert;May2010 Primary Care, p10 

    The article discusses a randomized placebo-controlled study conducted by P. W. Ladenson to examine the use of the Eprotirome (EPR), a thyroid hormone analogue, in statin-treated dyslipidemia.

Share

Read the Article

Courtesy of VIRGINIA BEACH PUBLIC LIBRARY AND SYSTEM

Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics