Structural characterization of β-catenin and RX-5902 binding to phospho-p68 RNA helicase by molecular dynamics simulation.

Emerging implications of probable ATP-dependent RNA helicase p68 in tumorigenesis and progression makes it a discerning target for cancer therapy. Recently it has been reported that tyrosyl-phosphorylation of p68 promotes β-catenin nuclear translocation and cancer metastasis through elevating the epithelial-mesenchymal transition. Despite recent advances, the structural characterization of this interaction, mode of action and induced conformational changes remain elusive. Here, through comparative structure analysis and molecular dynamics simulation assays, we explored comparative binding pattern of phospho-p68 against β-catenin. Conversely, due to the promising therapeutic potential of p68 in blocking the invasiveness and metastasis of cancer cells, we investigated the binding of heterocyclic N-substituted piperazine derivative-RX-5902 that inhibits the binding of phospho-p68 and β-catenin. Evidently, transactivation and C-terminal helicase domains of phospho-p68 exhibited dramatic conformational alterations to assist β-catenin and RX-5902 binding. As compared to unbound phospho-p68 (56.1 Å), the residual distances between transactivation domain-Ser79 and C-terminal helicase domain-Gln555 were reduced to 34.1 Å and 31 Å upon binding to β-catenin and RX-5902, respectively. In contrast, helicase ATP-binding domain remained conformationally stable throughout simulations. Clearly, the comparative docking-for-functional analysis of phospho-p68 against RX-5902 and β-catenin uncovered a spectrum of structural linkages associated with the molecular basis of β-catenin-dependent ATPase activity. Thus the outcomes of this study may provide a platform for the rational design of specific and potent inhibitors against phospho-p68 with a special emphasis on anticancer activity.