Exploring the mechanism of C473D mutation on CDC25B causing weak binding affinity with CDK2/CyclinA by molecular dynamics study

• Published in: Journal of biomolecular structure & dynamics Vol. 41; no. 22; pp. 12552 - 12564
• Main Authors: Li, Li-Peng, Li, Hao-Xin, Zhou, Hui, Li, Wei-Ya, Wang, Run-Ling, Zhang, Ying-Chi, Ma, Ying
• Format: Journal Article
• Language: English
• Published: England Taylor & Francis 29.12.2023
• Subjects: C473D mutation; CDC25B; CDK2/CyclinA; molecular dynamics study; weak binding affinity; weak binding affinity; C473D mutation; molecular dynamics study; CDK2/CyclinA; CDC25B
• ISSN: 0739-1102; 1538-0254
• DOI: 10.1080/07391102.2023.2166995

CDC25B belongs to the CDC25 family, and it plays an important part in regulating the activity of CDK/CyclinA. Studies have shown that CDC25B is closely related to cancer development. When CYS473 on CDC25B is mutated into ASP, the affinity between CDC25B and CDK2/CyclinA weakens, and their dissociation speed is greatly improved. However, the mechanism by which the CDC25B C473D mutant weakens its binding to CDK2/CyclinA is unclear. In order to study the effect of CDC25B C473D mutants on CDK2/CyclinA substrates, we constructed and verified the rationality of the CDC25B WT :CDK2/CyclinA system and CDC25B C473D :CDK2/CyclinA system and conducted molecular dynamics (MD) simulation analysis. In the post-analysis, the fluctuations of residues ARG488-SER499, LYS541-TRP550 on CDC25B and residues ASP206-ASP210 on CDK2 were massive in the mutant CDC25B C473D :CDK2/CyclinA system. And the interactions between residue ARG492 and residue GLU208, residue ARG544 and residue GLU42, residue ARG544 and TRP550 were weakened in the mutant CDC25B C473D :CDK2/CyclinA system. The results showed that when CYS473 on CDC25B was mutated into ASP473, the mutant CDC25B C473D :CDK2/CyclinA system was less stable than the wild-type CDC25B WT :CDK2/CyclinA system. Finally, active site CYS473 of CDC25B was speculated to be the key residue, which had great effects on the binding between CDC25B CYS473 and CDK2 in the CDC25B C473D :CDK2/CyclinA system. Consequently, overall analyses appeared in this study ultimately provided a useful understanding of the weak interactions between CDC25B CYS473D and CDK2/CyclinA. Communicated by Ramaswamy H. Sarma