title: Structural basis of GC-1 selectivity for thyroid hormone receptor isoforms.
abstract: BACKGROUND
  Thyroid receptors, TRalpha and TRbeta, 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 TRbeta isoform activation, TRalpha activation affects heart rates. Therefore, beta-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(c)) 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 TRalpha 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 TRbeta. The corresponding Arg282 of TRbeta 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 TRalpha, 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 TRbeta, in which it strongly interacts with both GC-1 and the Asn331.
  
  
  CONCLUSIONS
  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 beta-selectivity of GC-1 and may assist the development of new compounds with potential as drug candidates to the treatment of hypercholesterolemia and obesity.
authors.affiliation: Instituto de Física de São Carlos, Universidade de São Paulo, Avenida Trabalhador São Carlense, 400 CEP 13560-970 São Carlos, SP, Brazil. lbleicher@if.sc.usp.br
authors.forename: Lucas
authors.initials: L
authors.lastname: Bleicher
authors.forename: Ricardo
authors.initials: R
authors.lastname: Aparicio
authors.forename: Fabio M
authors.initials: FM
authors.lastname: Nunes
authors.forename: Leandro
authors.initials: L
authors.lastname: Martinez
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Gomes Dias
authors.forename: Ana Carolina Migliorini
authors.initials: AC
authors.lastname: Figueira
authors.forename: Maria Auxiliadora Morim
authors.initials: MA
authors.lastname: Santos
authors.forename: Walter H
authors.initials: WH
authors.lastname: Venturelli
authors.forename: Rosangela
authors.initials: R
authors.lastname: da Silva
authors.forename: Paulo Marcos
authors.initials: PM
authors.lastname: Donate
authors.forename: Francisco Ar
authors.initials: FA
authors.lastname: Neves
authors.forename: Luiz A
authors.initials: LA
authors.lastname: Simeoni
authors.forename: John D
authors.initials: JD
authors.lastname: Baxter
authors.forename: Paul
authors.initials: P
authors.lastname: Webb
authors.forename: Munir S
authors.initials: MS
authors.lastname: Skaf
authors.forename: Igor
authors.initials: I
authors.lastname: Polikarpov
mesh_terms: D000085:Acetates / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D006367:HeLa Cells; D006801:Humans; D008024:Ligands; D008954:Models, Biological; D010636:Phenols / Q000737:chemistry* / Q000378:metabolism; D020033:Protein Isoforms / Q000737:chemistry / Q000378:metabolism; D037021:Thyroid Hormone Receptors alpha / Q000737:chemistry* / Q000378:metabolism; D037042:Thyroid Hormone Receptors beta / Q000737:chemistry* / Q000378:metabolism
chemical_list: D000085:Acetates; C413355:GC 1 compound; D008024:Ligands; D010636:Phenols; D020033:Protein Isoforms; D037021:Thyroid Hormone Receptors alpha; D037042:Thyroid Hormone Receptors beta