20.500.12556/RUL-164416 Unveiling the interdomain dynamics of type II DNA topoisomerase through all-atom simulations implications for understanding its catalytic cycle Type IIA DNA topoisomerases are complex molecular nanomachines that manage topological states of the DNA molecule in the cell and play a crucial role in cellular processes such as cell division and transcription. They are also established targets of cancer chemotherapy. Starting from the available crystal structure of a fully catalytic topoisomerase IIA homodimer from Saccharomyces cerevisiae, we constructed three states of this molecular motor primarily changing the configurations of the DNA segment bound in the DNA gate and performed μs-long all-atom molecular simulations. A comprehensive analysis revealed a sliding motion within the DNA gate and a teamwork between the N-gate and DNA gate that may be associated with the necessary molecular events that allow passage of the T-segment of DNA. The observed movement of the ATPase dimer relative to the DNA domain was reflected in different interaction patterns between the K-loops of the transducer domain and the B-A-B form of the bound DNA. Based on the obtained results, we mapped simulated configurations to the structures in the proposed catalytic cycle through which type IIA topoisomerases exert their function and discussed the possible transition events. The results extend our understanding of the mechanism of action of type IIA topoisomerases and provide an atomistic interpretation of some of the observed features of these molecular motors. type IIA DNA topoisomerase catalytic cycle molecular simulations biokemija DNA topoizomeraza II[alfa] rakava obolenja kemoterapija molekularne simulacije true false true Angleški jezik Slovenski jezik Članek v reviji 2024-10-24 16:18:55 2024-10-24 16:18:56 2024-11-22 14:54:15 0000-00-00 00:00:00 2023 0 0 Str. 3746-3759 Vol. 21 2023 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 577 2001-0370 10.1016/j.csbj.2023.07.019 160446211 1-s2.0-S2001037023002593-main.pdf 1-s2.0-S2001037023002593-main.pdf 1 19CABAB9C8D3955DA1D39704A2C054CF 23ea345bf35d1920ef9a1670bc4785615114413b348703b557ba58c6415aae34 f2bdf750-9212-11ef-b232-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=194783 https://www.sciencedirect.com/science/article/pii/S2001037023002593 1 9b445fdb-9212-11ef-b232-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=194782 Fakulteta za farmacijo 0 0 0