Abstract
Mutations in the tumor suppressor protein p53 is a prevalent feature in majority of cancers resulting in inactivation of its activities related to control of cell cycle progression and proliferation. p53Y220C is one of the common hotspot mutations that causes decrease in its thermodynamic stability. Some small molecules have been shown to bind to the mutated site and restore its wild type thermodynamics and tumor suppressor function. In this study, we have explored the potential of caffeic acid phenethyl ester (CAPE—a bioactive compound from propolis) to interact with p53Y220C and restore its wild type p53 (p53wt) transcription activation and tumor suppressor activities. We recruited computational methods, viz. molecular docking, molecular dynamics simulations and free energy calculations to study the interaction of CAPE at the mutation crevice and found that it has potential to restore p53wt function of the p53Y220C mutant similar to a previously described restoration molecule PK7242. We provide cell-based experimental evidence to these predictions and suggest CAPE as a potential natural drug for treatment of p53Y220C mutant harboring cancers.
Highlights
Molecular analysis was done to analyze the docking of Caffeic acid phenethyl ester (CAPE) in PK7242-binding site/mutation crevice of p53Y220C
PK7242 was re-docked into the mutation crevice of p 53Y220C, and the binding pose obtained was compared with pose in the crystal structure to check for the closeness
In this study we explored the potential of CAPE to restore the function of structurally unstable p53Y220C
Summary
p53Y220C mutant contains a unique surface crevice, formed due to the replacement of tyrosine with cysteine at 220th amino acid residue position [9] The solvation of this crevice decreases the thermodynamical stability and the activity of the protein [10, 11]. Other approaches like introduction of mutation at secondary site [14], use of antibodies [15, 16] or short peptides [17, 18] have been reported to restore DNA binding in the mutant p53 protein resulting in activation of its transcriptional and tumor suppressor functions. A previous study from our group has shown the potential of withanolides, withaferin-A and withanone, in restoring the wild type p53 activity in p53Y220C mutant harboring cancer cells [19]
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