Structural basis for gate-DNA recognition and bending by type IIA topoisomerases
Structural basis for gate-DNA recognition and bending by type IIA topoisomerases
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DOI：
10.1038/nature06396
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发表时间：
2007-12-20
期刊：
影响因子：
64.8
通讯作者：
Berger, James M.
中科院分区：
文献类型：
--
作者：
Dong, Ken C.;Berger, James M.
II型拓扑异构酶解开DNA以促进染色体分离，并且代表了一类主要的治疗靶标。虽然这些酶已被广泛研究，但缺乏对DNA结合的分子理解。在这里，我们提出了一个复杂的结构之间的DNA结合和切割核心的酿酒酵母拓扑结构II（也称为Top2）和门DNA片段。该结构揭示了该酶通过类似于重塑蛋白质如整合宿主因子的机制来强制150度DNA弯曲。大的蛋白质构象变化伴随着DNA变形，产生一个二分催化位点，将DNA骨架定位在活性酪氨酸和配位镁离子附近。这种结构非常类似于IA型拓扑异构酶的催化位点，加强了这些结构和功能不同的酶之间的进化联系。DNA的结合促进了酶二聚化界面的打开，为DNA转运中的关键步骤提供了视觉证据。
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 degrees 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.