RESUMEN
Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear receptor with a key role in metabolic processes and is target of CDK5 kinase phosphorylation at S245 (S273 in PPARγ isoform 2), thereby inducing insulin resistance. A remarkable effort has been addressed to find PPARγ ligands that inhibit S245 phosphorylation, but the poor understanding in this field challenges the design of such ligands. Here, through computational and biophysical methods, we explored an experimentally validated model of PPARγ-CDK5 complex, and we presented K261, K263 or K265, which are conserved in mammals, as important anchor residues for this interaction. In addition, we observed, from structural data analysis, that PPARγ ligands that inhibit S245 phosphorylation are not in direct contact with these residues; but induce structural modifications in PPARγ:CDK5/p25 interface. In summary, our PPARγ and CDK5/p25 interaction analyses open new possibilities for the rational design of novel inhibitors that impair S245 phosphorylation.
Asunto(s)
Quinasa 5 Dependiente de la Ciclina/química , Complejos Multiproteicos/química , PPAR gamma/química , Conformación Proteica , Animales , Sitios de Unión/genética , Quinasa 5 Dependiente de la Ciclina/genética , Quinasa 5 Dependiente de la Ciclina/metabolismo , Humanos , Ligandos , Modelos Moleculares , Complejos Multiproteicos/genética , Complejos Multiproteicos/metabolismo , Mutación , PPAR gamma/genética , PPAR gamma/metabolismo , Fosforilación , Unión ProteicaRESUMEN
Previous research found that when Body Mass Index (BMI) was statistically controlled in a multiple regression model, the percentage of body fat accounted for no additional variance in dietary restraint scores among women although, on its own, it was a significant predictor of this variable. These results imply that anatomical factors, besides fatness, influence dieting behaviour. The present study was designed to compare the relative influence on dietary restraint and weight dissatisfaction, of three body composition measures, each of which contributes in a different way to subjective impressions of body size (viz. BMI, body fat content, and skeletal frame size). Measures of emotional reactivity ('neuroticism'), body dissatisfaction, , and body focus were also included in the regression model. Results indicated that these psychological variables were strongly and positively related to restraint. Frame size was also a significant predictor of restraint and weight dissatisfaction. In fact, when frame size was controlled in the regression model, neither percentage of body fat nor BMI were able to explain any additional variance in restraint scores. These findings indicate that weight concerns and dieting behaviour are influenced, at least among young women, more by the size of their skeletal structure than their degree of adiposity. The irony of these findings is obvious and disheartening. An anatomical feature which is essentially resistant to change by dieting or exercise appears to be a primary influence in women's weight dissatisfaction and their tendency to diet. It is acknowledged, however, that this relationship may not obtain among very obese women.