| Texto completo | |
| Autor(es): |
Gutierrez, Alvaro
;
Ferreira, Glaucio Monteiro
;
Machuca, Juan
;
Venthur, Herbert
;
Feres, Fausto
;
Hirata, Mario Hirouyki
;
Hirata, Rosario Dominguez Crespo
;
Cerda, Alvaro
Número total de Autores: 8
|
| Tipo de documento: | Artigo Científico |
| Fonte: | Journal of Molecular Modeling; v. 26, n. 10, p. 9-pg., 2020-09-25. |
| Resumo | |
Adenovirus 36 (Ad-36) is related to human obesity due to its adipogenic activity mediated by the early 4 open reading frame 1 (E4orf1) protein. Mechanisms underlying the adipogenic effect of E4orf1 are not completely understood; however, the proliferation and differentiation of fat cells are increased through the activation of the phosphatidyl inositol 3 kinase pathway by binding proteins containing PDZ domain. This study characterized E4orf1 tridimensional structure and analyzed its interactions with PDZ domain-containing proteins in order to provide new information about the behavior of this viral protein and its targets, which could provide an interesting druggable target for obesity-related cardiometabolic alterations. In silico strategies such as homology modeling, docking, and molecular dynamics (MD) were used to study the interaction of E4orf1 with five PDZ domains of disk large homolog 1 (PDZ-1 and PDZ-2), membrane-associated guanylate kinase 1 (PDZ-3), and multi-PDZ domain protein 1 (PDZ-7 and PDZ-10). Mutagenesis analysis of selected residues was performed to evaluate their effects on the stabilization of E4orf1:PDZ complexes. MD simulations showed that the E4orf1:PDZ10 complex was more stable than the others ones. The highly hydrophobic residues at the C-terminal region (114-125) of the E4orf1 are essential in the initial phase stabilization of the complexes. Moreover, the residues 80-85 in the core region contribute to longer stabilization of the E4orf1:PDZ10 complex, a result that was confirmed by in silico mutagenesis. In conclusion, E4orf1 forms a stable complex with PDZ10 domain, and the residues 80-85 are of particular importance. The characterization of E4orf1 interactions with PDZ domains provides an initial approach to discover druggable targets for Ad-36-induced obesity. (AU) | |
| Processo FAPESP: | 19/06172-4 - Bolsa de PD em busca de novos fármacos contra Hipercolesterolemia, baseados em marcadores genéticos e epigenéticos específicos da população brasileira |
| Beneficiário: | Glaucio Monteiro Ferreira |
| Modalidade de apoio: | Bolsas no Brasil - Pós-Doutorado |