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Open Access Research article

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

Lucas Bleicher1, Ricardo Aparicio2, Fabio M Nunes1, Leandro Martinez2, Sandra M Gomes Dias3, Ana Carolina Migliorini Figueira1, Maria Auxiliadora Morim Santos1, Walter H Venturelli4, Rosangela da Silva5, Paulo Marcos Donate4, Francisco AR Neves6, Luiz A Simeoni6, John D Baxter7, Paul Webb7, Munir S Skaf2 and Igor Polikarpov1*

Author Affiliations

1 Instituto de Física de São Carlos, Universidade de São Paulo, Avenida Trabalhador São Carlense, 400 CEP 13560-970 São Carlos, SP, Brazil

2 Instituto de Química, Universidade Estadual de Campinas, Caixa Postal 6154, 13084-862 Campinas, SP, Brazil

3 C3-137, Molecular Medicine Department, College of Veterinary Medicine, Cornell University, Ithaca, NY, ZIP 14853, USA

4 Departamento de Química, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, Avenida Bandeirantes n. 3900, 14040-901, Ribeirão Preto, SP. Brazil

5 Núcleo de Pesquisa em Ciências Exatas e Tecnológicas, Universidade de Franca, Avenida Dr. Arnaldo Salles de Oliveira, 2001, 14404-600, Franca, SP, Brazil

6 Departamento de Ciências Farmacêuticas, Universidade de Brasília, Brasília, DF, 70900-910l, Brazil

7 Diabetes Center, Metabolic Research Unit, and the Department of Medicine, University of California San Francisco, San Francisco CA, 94143, USA

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BMC Structural Biology 2008, 8:8  doi:10.1186/1472-6807-8-8

Published: 31 January 2008

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.