Year: 2025
Type: article
Abstract: , particularly within its DNA-binding domain, are among the most frequent genetic alterations in human cancers and are strongly associated with chemoresistance and poor prognosis. In this study, all TP53 mutations reported in the COSMIC database were systematically mapped onto all experimentally resolved TP53 three-dimensional structures available in the Protein Data Bank, supplemented with AlphaFold-predicted models to achieve full structural coverage. Mutations were classified according to their structural context-protein core, interface regions, ligand- and zinc-binding sites, and intrinsically disordered regions-and evaluated using complementary sequence- and structure-based predictive tools. The analysis revealed distinct mutational hotspots, differential distribution across structural regions, and context-dependent effects on stability and DNA-binding capacity. Notably, a subset of mutations exhibited consistent predictions of high destabilisation across all structural contexts, underscoring their potential as drivers of functional inactivation. By providing a comprehensive structural map of TP53 alterations, this work offers a valuable resource for understanding mutation-specific mechanisms of p53 dysfunction and for guiding the development of precision therapeutic strategies aimed at restoring its tumour-suppressive functions.
DOI: 10.3390/ijms26189135
Author: Ali F. Alsulami
Institution: King Abdulaziz University
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,499
Funder: King Abdulaziz University
OpenAlex ID: W4414356589