Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 23, Issue 23, Pages -Publisher
MDPI
DOI: 10.3390/ijms232315267
Keywords
p53; cancer; molecular modeling; tumor suppressor; apoptosis; DNA repair
Funding
- National Institutes of Health
- National Cancer Institute [R01CA193578, R01CA227261, R01CA219700]
- Center for Structural Oncology at the Huck Institutes of the Life Sciences, Pennsylvania State University
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Genetic mutations in tumor suppressor genes can lead to cancer, with mutations in p53 potentially exacerbating toxic effects and impeding DNA interactions, emphasizing the need for new studies to assist in redesigning targeted therapies based on protein structure.
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.
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