20.500.12556/RUL-140838 Catalytic mechanism of ATP hydrolysis in the ATPase domain of human DNA topoisomerase IIα Human DNA topoisomerase IIα is a biological nanomachine that regulates the topological changes of the DNA molecule and is considered a prime target for anticancer drugs. Despite intensive research, many atomic details about its mechanism of action remain unknown. We investigated the ATPase domain, a segment of the human DNA topoisomerase IIα, using all-atom molecular simulations, multiscale quantum mechanics/molecular mechanics (QM/MM) calculations, and a point mutation study. The results suggested that the binding of ATP affects the overall dynamics of the ATPase dimer. Reaction modeling revealed that ATP hydrolysis favors the dissociative substrate-assisted reaction mechanism with the catalytic Glu87 serving to properly position and polarize the lytic water molecule. The point mutation study complemented our computational results, demonstrating that Lys378, part of the important QTK loop, acts as a stabilizing residue. The work aims to pave the way to a deeper understanding of these important molecular motors and to advance the development of new therapeutics. biokemija DNK topoizomeraze simulacije true false true Angleški jezik Slovenski jezik Članek v reviji 2022-09-19 15:15:15 2022-09-19 15:15:16 2022-09-24 04:12:17 0000-00-00 00:00:00 2022 0 0 Str. 3896–3909 iss. 16 Vol. 62 Aug. 2022 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 577 1549-9596 10.1021/acs.jcim.2c00303 120437251 acs.jcim.2c00303_Catalytic_Mechanism_of_ATP_Hydrolysis_in_the_ATPase_Domain_of_Human_DNA_Topoisomerase_II.pdf acs.jcim.2c00303_Catalytic_Mechanism_of_ATP_Hydrolysis_in_the_ATPase_Domain_of_Human_DNA_Topoisomerase_II.pdf 1 FE5940940454646C8171111C1C268724 c4d114982d846f76da4b8d563dabdba09e2c3750448e744efb45462f3af374b2 d569b154-3b28-11ed-9c94-00155dcfd717 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=162065 https://pubs.acs.org/doi/10.1021/acs.jcim.2c00303 0 06897fc9-381d-11ed-92af-00155dcfd717 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=161648 Fakulteta za farmacijo 0 0 0