| Περίληψη: | The transcription factors of FOXO family and the tumor suppressing proteins of p53 have been put under the microscope of pharmaceutical research, since they are involved in the regulation of several signaling pathways related to the DNA repair, the cell cycle arrest and the activation of apoptosis. There are indications that FOXO4 and p53 bind each other within the nucleus of senescent cells promoting the transcription of p21 (cell cycle inhibitor). Recently, it has been shown that inhibition of FOXO4-p53 interaction promotes apoptosis in senescent cells. Inevitably, this interaction has been characterized as biological target in terms of its anti-aging (senolytic) effect. The exact structure of this complex has not been resolved yet experimentally, owing to the highly dynamic regions of these two proteins. However, knowledge of the interaction interface of this complex is of paramount importance for the development of small molecules that could inhibit formation of the complex.
The scope of this investigation is to provide rational models of the p53/FOXO4 complex based on experimental evidence. First, we collected biochemical, biophysical and structural information, including the available X-ray and NMR structures of isolated FOXO4 and p53 domains. These data were analyzed to select appropriate structural templates for the modeling of putative p53/FOXO4 complexes with different orientations and initial conformations. Based on the calculated free energy of binding, we selected the most favored models that satisfied experimental constraints. These models were evaluated by means of stability in solvent using classical molecular dynamics simulations (MD). The favored models of p53/FOXO4 complex were also investigated in the presence of double-stranded DNA fragments that correspond to response elements of p21 promoter, with the aim to identify the most appropriate p53/FOXO4 models. As a result, we propose a rational p53/FOXO4 complex that is compatible with the pre-initiation complex of p21 gene.
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