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

DOI: 10.1038/s41467-018-05005-x DOI Help

Authors: Ivan Laponogov (King's College London; St. George’s, University of London) , Xiao-su Pan (King’s College London; St. George’s, 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 (St. George’s, University of London) , Mark Sanderson (King's College London)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Communications , VOL 9

State: Published (Approved)
Published: July 2018
Diamond Proposal Number(s): 1220 , 7656 , 9495

Open Access Open Access

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.

Journal Keywords: DNA recombination; X-ray crystallography

Subject Areas: Biology and Bio-materials, Medicine

Instruments: I02-Macromolecular Crystallography , I03-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength) , I04-Macromolecular Crystallography , I24-Microfocus Macromolecular Crystallography