Restoration of the Y220C p53 Full-Length Mutant by PK11000: a Molecular Dynamics Study of an Intrinsically Disordered Protein.

ABSTRACT: The tumor suppressor protein p53 plays a key role in cellular homeostasis, with its dysfunction linked to over half of all cases of human cancer. The Y220C mutation in the DNA-binding domain (DBD) destabilizes p53, compromising its function. The most well-studied case of Y220C p53 rescue via a small molecule, PK11000, has been shown to restore stability and reinstate activity both in vitro and in vivo in rodent models. While prior in silico studies have focused on the DBD in isolation, this work explores the full-length p53 protein, incorporating its intrinsically disordered N- and C-terminal regulatory regions, which are known to be sites of extensive post-translational modifications utilized to modulate its activity. Using molecular dynamics (MD) simulations, we investigate the wild-type (WT) p53, the destabilized Y220C mutant, and the PK11000-rescued Y220C variant. Our findings illuminate a multilayered allosteric landscape: the Y220C mutation disrupts DBD stability through long-range effects while PK11000 counteracts this destabilization through its own distal interactions. Importantly, the N- and C-terminal regions mediate additional allosteric regulation, dynamically influencing both the mutation's impact and the rescue mechanism. This triple allosteric framework underscores the regulatory regions' critical role in restoring p53 functionality. By providing a first-order exploration into the behavior of full-length p53, this study advances our understanding of its regulatory mechanisms and sets the stage for developing targeted therapies aimed at reactivating mutant p53 in cancer.

SUBMITTER: Stetson S 

PROVIDER: S-EPMC12809809 | biostudies-literature | 2026 Jan

REPOSITORIES: biostudies-literature