Type II DNA topoisomerase (topo II) is a molecular machine that utilizes adenosine triphosphate (ATP) to transport one DNA duplex through another. The enzyme catalytic activity can be inhibited by a variety of small molecules including bisdioxopiperazines. In the presence of the non-hydrolyzable ATP anolog adenosine 5'-[β,γ-imino] triphosphate (ADPNP), the enzyme allows only one round of DNA transport. A mechanistic understanding of the mechanisms of enzym action and drug inhibition is achieved by applying a nucleotide- dependent elastic network model. In our coarse-grained analysis of the topo II holoenzyme, a structural model which combines crystallographic structures of the 45-kDa ATPase fragment and the 92-kDa topo II fragment is used. The computation results show that in a catalytic cycle the binding and hydrolyzing ATP couples two low-frequency normal modes (v2 and v5). As such, the enzyme drives its conformational gatings to transport DNA in a concerted manner. The bisdioxopiperazine or ADPNP binding also initially activates these two low-frequency modes. However, topo II fails in completing a catalytic cycle due to the non-hydrolyzable property of these small molecules, thus the enzyme activity is inhibited.
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