Complete Models of p53 Better Inform the Impact of Hotspot Mutations

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 impac...

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Bibliographic Details
Published inInternational journal of molecular sciences Vol. 23; no. 23; p. 15267
Main Authors Solares, Maria J, Kelly, Deborah F
Format Journal Article
LanguageEnglish
Published Switzerland MDPI AG 03.12.2022
MDPI
Subjects
Amino acids
Apoptosis
Cancer
Cellular structure
Communication
Computer applications
Deoxyribonucleic acid
DNA
DNA - chemistry
DNA damage
DNA repair
DNA-Binding Proteins - metabolism
Gene expression
Genes, p53
Humans
Missense mutation
molecular modeling
Mutation
Mutation hot spots
Neoplasms - genetics
p53
p53 Protein
Phenotypes
Proteins
Structural models
Suppressors
tumor suppressor
Tumor suppressor genes
Tumor Suppressor Protein p53 - metabolism
Tumors
Zinc coordination
apoptosis
tumor suppressor
cancer
molecular modeling
DNA repair
p53
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Summary: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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ISSN:1422-0067
1661-6596
1422-0067
DOI:10.3390/ijms232315267