期刊
JOURNAL OF MOLECULAR BIOLOGY
卷 424, 期 3-4, 页码 109-124出版社
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jmb.2012.07.014
关键词
type IIA topoisomerase; allostery; double-strand DNA breaks; protein-drug interactions; chemotherapeutics
资金
- National Science Foundation [DGE 1106400]
- Leukaemia Lymphoma Research grant [07038]
- National Cancer Institute [CA077373]
Type II topoisomerases are required for the management of DNA superhelicity and chromosome segregation, and serve as frontline targets for a variety of small-molecule therapeutics. To better understand how these enzymes act in both contexts, we determined the 2.9-angstrom-resolution structure of the DNA cleavage core of human topoisomerase II alpha (TOP2A) bound to a doubly nicked, 30-bp duplex oligonucleotide. In accord with prior biochemical and structural studies, TOP2A significantly bends its DNA substrate using a bipartite, nucleolytic center formed at an N-terminal dimerization interface of the cleavage core. However, the protein also adopts a global conformation in which the second of its two inter-protomer contact points, one at the C-terminus, has separated. This finding, together with comparative structural analyses, reveals that the principal site of DNA engagement undergoes highly quantized conformational transitions between distinct binding, cleavage, and drug-inhibited states that correlate with the control of subunit-subunit interactions. Additional consideration of our TOP2A model in light of an etoposide-inhibited complex of human topoisomerase II beta (TOP2B) suggests possible modification points for developing paralog-specific inhibitors to overcome the tendency of topoisomerase II-targeting chemotherapeutics to generate secondary malignancies. (C) 2012 Elsevier Ltd. All rights reserved.
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