Trapping of the transport-segment DNA by the ATPase domains of a type II topoisomerase

Ivan Laponogov, Xiao-Su Pan, Dennis A. Veselkov, Galyna B. Skamrova, Trishant R. Umrekar, L. Mark Fisher () and Mark R. Sanderson ()
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Ivan Laponogov: King’s College London
Xiao-Su Pan: University of London
Dennis A. Veselkov: King’s College London
Galyna B. Skamrova: King’s College London
Trishant R. Umrekar: King’s College London
L. Mark Fisher: University of London
Mark R. Sanderson: King’s College London

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: Abstract Type II topoisomerases alter DNA topology to control DNA supercoiling and chromosome segregation and are targets of clinically important anti-infective and anticancer therapeutics. They act as ATP-operated clamps to trap a DNA helix and transport it through a transient break in a second DNA. Here, we present the first X-ray crystal structure solved at 2.83 Å of a closed clamp complete with trapped T-segment DNA obtained by co-crystallizing the ATPase domain of S. pneumoniae topoisomerase IV with a nonhydrolyzable ATP analogue and 14-mer duplex DNA. The ATPase dimer forms a 22 Å protein hole occupied by the kinked DNA bound asymmetrically through positively charged residues lining the hole, and whose mutagenesis impacts the DNA decatenation, DNA relaxation and DNA-dependent ATPase activities of topo IV. These results and a side-bound DNA-ParE structure help explain how the T-segment DNA is captured and transported by a type II topoisomerase, and reveal a new enzyme–DNA interface for drug discovery.

Date: 2018
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DOI: 10.1038/s41467-018-05005-x

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