Drug-Induced Conformational Population Shifts in Topoisomerase-DNA Ternary Complexes
AbstractType II topoisomerases (TOP2) are enzymes that resolve the topological problems during DNA replication and transcription by transiently cleaving both strands and forming a cleavage complex with the DNA. Several prominent anti-cancer agents inhibit TOP2 by stabilizing the cleavage complex and engendering permanent DNA breakage. To discriminate drug binding modes in TOP2-α and TOP2-β, we applied our newly developed scoring function, dubbed AutoDock4RAP, to evaluate the binding modes of VP-16, m-AMSA, and mitoxantrone to the cleavage complexes. Docking reproduced crystallographic binding mode of VP-16 in a ternary complex of TOP2-β with root-mean-square deviation of 0.65 Å. Molecular dynamics simulation of the complex confirmed the crystallographic binding mode of VP-16 and the conformation of the residue R503. Drug-related conformational changes in R503 have been observed in ternary complexes with m-AMSA and mitoxantrone. However, the R503 rotamers in these two simulations deviate from their crystallographic conformations, indicating a relaxation dynamics from the conformations determined with the drug replacement procedure. The binding mode of VP-16 in the cleavage complex of TOP2-α was determined by the conjoint use of docking and molecular dynamics simulations, which fell within a similar binding pocket of TOP2-β cleavage complex. Our findings may facilitate more efficient design efforts targeting TOP2-α specific drugs. View Full-Text
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Huang, N.-L.; Lin, J.-H. Drug-Induced Conformational Population Shifts in Topoisomerase-DNA Ternary Complexes. Molecules 2014, 19, 7415-7428.
Huang N-L, Lin J-H. Drug-Induced Conformational Population Shifts in Topoisomerase-DNA Ternary Complexes. Molecules. 2014; 19(6):7415-7428.Chicago/Turabian Style
Huang, Nan-Lan; Lin, Jung-Hsin. 2014. "Drug-Induced Conformational Population Shifts in Topoisomerase-DNA Ternary Complexes." Molecules 19, no. 6: 7415-7428.