1. Chemical Biology Graduate Program, Department of Chemistry, College of Chemistry, University of California, Berkeley, California 94720-3220, USA
2. Division of Biochemistry and Molecular Biology, Department of Molecular and Cell Biology, QB3 Institute, Stanley Hall 3220, University of California at Berkeley, Berkeley, California 94720-3220, USA

Correspondence to: James M. Berger² Correspondence and requests for materials should be addressed to J.M.B. (Email: jmberger@berkeley.edu).

Abstract

Type II topoisomerases disentangle DNA to facilitate chromosome segregation, and represent a major class of therapeutic targets. Although these enzymes have been studied extensively, a molecular understanding of DNA binding has been lacking. Here we present the structure of a complex between the DNA-binding and cleavage core of Saccharomyces cerevisiae Topo II (also known as Top2) and a gate-DNA segment. The structure reveals that the enzyme enforces a 150° DNA bend through a mechanism similar to that of remodelling proteins such as integration host factor. Large protein conformational changes accompany DNA deformation, creating a bipartite catalytic site that positions the DNA backbone near a reactive tyrosine and a coordinated magnesium ion. This configuration closely resembles the catalytic site of type IA topoisomerases, reinforcing an evolutionary link between these structurally and functionally distinct enzymes. Binding of DNA facilitates opening of an enzyme dimerization interface, providing visual evidence for a key step in DNA transport.

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