Analysis of E2F1 single-nucleotide polymorphisms reveals deleterious non-synonymous substitutions that disrupt E2F1-RB protein interaction in cancer.
PMID 38242392 | DOI 10.1016/j.ijbiomac.2024.129559 · International journal of biological macromolecules · 2024
Cancer is a medical condition that is caused by the abnormal growth and division of cells, leading to the formation of tumors. The E2F1 and RB pathways are critical in regulating cell cycle, and their dysregulation can contribute to the development of cancer. In this study, we analyzed experimentally reported SNPs in E2F1 and assessed their effects on the binding affinity with RB. Out of 46, nine mutations were predicted as deleterious, and further analysis revealed four highly destabilizing mutations (L206W, R232C, I254T, A267T) that significantly altered the protein structure. Molecular docking of wild-type and mutant E2F1 with RB revealed a docking score of -242 kcal/mol for wild-type, while the mutant complexes had scores ranging from -217 to -220 kcal/mol. Molecular simulation analysis revealed variations in the dynamics features of both mutant and wild-type complexes due to the acquired mutations. Furthermore, the total binding free energy for the wild-type E2F1-RB complex was -64.89 kcal/mol, while those of the L206W, R232C, I254T, and A267T E2F1-RB mutants were -45.90 kcal/mol, -53.52 kcal/mol, -55.67 kcal/mol, and -61.22 kcal/mol, respectively. Our study is the first to extensively analyze E2F1 gene mutations and identifies candidate mutations for further validation and potential targeting for cancer therapeutics.
Validated evidence
| Type | Entity | Source evidence | Confidence | Extractor |
|---|---|---|---|---|
| gene | E2F1 | “Analysis of E2F1 single-nucleotide polymorphisms reveals deleterious non-synonymous substitutions that disrupt E2F1-RB protein interaction in cancer.” | 0.98 | hgnc_dict_v1 |
| variant | L206W | “Out of 46, nine mutations were predicted as deleterious, and further analysis revealed four highly destabilizing mutations (L206W, R232C, I254T, A267T) that significantly altered the protein structure.” | 0.82 | literature_variant_regex_v2 |
| variant | R232C | “Out of 46, nine mutations were predicted as deleterious, and further analysis revealed four highly destabilizing mutations (L206W, R232C, I254T, A267T) that significantly altered the protein structure.” | 0.82 | literature_variant_regex_v2 |
| variant | I254T | “Out of 46, nine mutations were predicted as deleterious, and further analysis revealed four highly destabilizing mutations (L206W, R232C, I254T, A267T) that significantly altered the protein structure.” | 0.82 | literature_variant_regex_v2 |
| variant | A267T | “Out of 46, nine mutations were predicted as deleterious, and further analysis revealed four highly destabilizing mutations (L206W, R232C, I254T, A267T) that significantly altered the protein structure.” | 0.82 | literature_variant_regex_v2 |