Structural basis of GC-1 selectivity for thyroid hormone receptor isoforms.
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.
Bleicher
Lucas
L
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
Aparicio
Ricardo
R
Nunes
Fabio M
FM
Martinez
Leandro
L
Gomes Dias
Sandra M
SM
Figueira
Ana Carolina Migliorini
AC
Santos
Maria Auxiliadora Morim
MA
Venturelli
Walter H
WH
da Silva
Rosangela
R
Donate
Paulo Marcos
PM
Neves
Francisco Ar
FA
Simeoni
Luiz A
LA
Baxter
John D
JD
Webb
Paul
P
Skaf
Munir S
MS
Polikarpov
Igor
I
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
D000085:Acetates; C413355:GC 1 compound; D008024:Ligands; D010636:Phenols; D020033:Protein Isoforms; D037021:Thyroid Hormone Receptors alpha; D037042:Thyroid Hormone Receptors beta