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Analysis of E2F1 single-nucleotide polymorphisms reveals deleterious non-synonymous substitutions that disrupt E2F1-RB protein interaction in cancer.
Suleman, Muhammad; Khattak, Aishma; Akbar, Fazal; Rizwan, Muhammad; Tayyab, Muhammad; Yousaf, Muhammad; Khan, Abbas; Albekairi, Norah A; Agouni, Abdelali; Crovella, Sergio.
Afiliación
  • Suleman M; Laboratory of Animal Research Center (LARC) Qatar University, Doha, Qatar; Center for Biotechnology and Microbiology, University of Swat, Swat, Pakistan. Electronic address: suleman@uswat.edu.pk.
  • Khattak A; Department of Bioinformatics, Shaheed Benazir butto women university Peshawar, Pakistan.
  • Akbar F; Center for Biotechnology and Microbiology, University of Swat, Swat, Pakistan. Electronic address: fazalakbar@uswat.edu.pk.
  • Rizwan M; Center for Biotechnology and Microbiology, University of Swat, Swat, Pakistan. Electronic address: rizwan@uswat.edu.pk.
  • Tayyab M; Institute of Biotechnology and Genetic Engineering, the University of Agriculture Peshawar. Electronic address: muhammadtayyab@aup.edu.pk.
  • Yousaf M; Centre for Animal Sciences and Fisheries, University of Swat, Swat, Pakistan. Electronic address: dyousaf@uswat.edu.pk.
  • Khan A; Department of Bioinformatics and Biostatistics, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China. Electronic address: abbaskhan@sjtu.edu.cn.
  • Albekairi NA; Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Post Box 2455, Riyadh 11451, Saudi Arabia. Electronic address: nalbekairi@ksu.edu.sa.
  • Agouni A; Department of Pharmaceutical Sciences, College of Pharmacy, QU Health, Qatar University, P.O. Box 2713, Doha, Qatar. Electronic address: aagouni@qu.edu.qa.
  • Crovella S; Laboratory of Animal Research Center (LARC) Qatar University, Doha, Qatar. Electronic address: sgrovella@qu.edu.qa.
Int J Biol Macromol ; 260(Pt 1): 129559, 2024 Mar.
Article en En | MEDLINE | ID: mdl-38242392
ABSTRACT
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.
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Texto completo: 1 Base de datos: MEDLINE Asunto principal: Proteína de Retinoblastoma / Neoplasias Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Int J Biol Macromol Año: 2024 Tipo del documento: Article

Texto completo: 1 Base de datos: MEDLINE Asunto principal: Proteína de Retinoblastoma / Neoplasias Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Int J Biol Macromol Año: 2024 Tipo del documento: Article