Characterizing p53 structural insights of variants in vertebrates that interfere its regulatory interaction with Mdm2

Abstract

The tumor suppressor p53, transcriptionally regulates several target genes, and in the absence of cellular stress its basal protein levels are tightly regulated by Mdm2 (Murine double minute 2). Species with functional p53 are less prone to cancer, and in mammals this oncogene has a multifunctional role towards cancer tolerance. Herein, we examined naturally evolving p53 protein across vertebrates with its negative regulator, along with exploring their structural properties. Several mammalian species contain conserved p53 amphipathic α-helical BOX-I, DNA-binding domain (DBD), and basic domains, whereas Loxodonta africana (elephant) exhibits the lowest sequence similarities. Vertebrates with notable insertion in the DBD or disordered BOX-I regions gained a unique structural orientation, that can potentiate to escape Mdm2 negative regulation. Comprehending molecular details, we constructed an Mdm2 pharmacophore model that can interact with a specific set of p53 isoforms. To explore potential use of BOX-I derived linear motifs as peptidomimetic molecules targeting Mdm2 we assessed their binding affinity, as well as the effect of temperature over the p53-Mdm2 complex. Conformational changes adopted by p53 variants identify crucial residues within the FxxxW/GxxL motif. These residues face the Mdm2 pocket and may enhance binding affinity, even under thermal change. Mdm2 was found mutated heavily in carcinoma, and its variant can have a significant role when associating with p53. Our findings demonstrate a natural living model, to utterly contribute to the mechanistic understanding of the role of p53 in its activation, giving insight on structural properties aiming to target these biomarkers in cancer therapeutics.