Complete Models of p53 Better Inform the Impact of Hotspot Mutations

Abstract

Mutations in tumor suppressor genes often lead to cancerous phenotypes. Current treatments leverage signaling pathways that are often compromised by disease-derived deficiencies in tumor suppressors. P53 falls into this category as genetic mutations lead to physical changes in the protein that impact multiple cellular pathways. Here, we show the first complete structural models of mutated p53 to reveal how hotspot mutations physically deviate from the wild-type protein. We employed a recently determined structure for the p53 monomer to map seven frequent clinical mutations using computational modeling approaches. Results showed that missense mutations often changed the conformational structure of p53 in the DNA-binding site along with its electrostatic surface charges. We posit these changes may amplify the toxic effects of these hotspot mutations by destabilizing an important zinc ion coordination region in p53 to impede proper DNA interactions. These results highlight the imperative need for new studies on patient-derived proteins that may assist in redesigning structure-informed targeted therapies.