Science Advances, 17 December, 2025, DOI：https://doi.org/10.1126/sciadv.adw2839

Direct trapping of the transport-segment DNA by the central domain of type IIA topoisomerases

Yuhui Xin, Runqi Xian, Congrong Liu, Oujia Zhang, Zihe Rao, Xuemei Li, and Yutao Chen

Abstract

Type IIA topoisomerases modulate DNA topology by coordinating the cleavage of gate-segment DNA and the passage of transport-segment DNA—a mechanism conserved across species and essential for diverse cellular processes. While gate-segment interactions have been extensively studied, direct structural evidence of transport-segment capture has remained elusive, limiting our understanding of the full catalytic cycle. Here, we present a cryo–electron microscopy structure of the T4 bacteriophage topoisomerase II with a transport-segment DNA bound directly to its central domain. The structure reveals conformational rearrangements in the central domain that accommodate the transport-segment DNA, suggesting an alternative sequence of events in which the enzyme sliding along the loosely bound religated gate segment may precede transport-segment passage through the coiled-coil gate. Supported by mutational and biochemical assays, our findings provide previously unidentified mechanistic insights and open potential avenues for the development of next-generation type IIA topoisomerase inhibitors.

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