New insights into DNA-binding by type IIA topoisomerases

► The WHD of type IIA topoisomerases exhibits a non-canonical DNA-binding mode. ► Packing of the two WHDs defines the cleavage pattern of type IIA topoisomerases. ► The wing-2 region of IIA enzyme's WHD mediates G-segment-bending. ► The Rossmann-like TOPRIM domain involves in catalysis as well as DNA-binding. ► The IIA enzyme–DNA interface can be targeted by antibiotics and anticancer drugs. Type IIA topoisomerases catalyze the passage of two DNA duplexes across each other to resolve the entanglements and coiling of cellular DNA. The ability of these enzymes to interact simultaneously but differentially with two DNA segments is central to their DNA-manipulating functions: one duplex DNA is bound and cleaved to produce a transient double-strand break through which another DNA segment can be transported. Recent structural analyses have revealed in atomic detail how type IIA enzymes contact DNA and how the enzyme–DNA interactions may be exploited by drugs to achieve therapeutic purposes. This review summarizes these new findings, with a special focus on the assembly and structural features of the enzymes’ composite DNA-binding surfaces.