4FM9

Human topoisomerase II alpha bound to DNA

Summary for 4FM9

• Entry DOI: 10.2210/pdb4fm9/pdb
• Descriptor: DNA topoisomerase 2-alpha, DNA (5'-D(P*GP*AP*GP*GP*AP*TP*GP*AP*CP*GP*AP*TP*G)-3'), DNA (5'-D(*CP*GP*CP*GP*CP*AP*TP*CP*GP*TP*CP*AP*TP*CP*CP*TP*C)-3'), ... (6 entities in total)
• Functional Keywords: topoisomerase, dna-binding, protein-dna complex, isomerase-dna complex, isomerase/dna
• Biological source: Homo sapiens (human); More
• Cellular location: Cytoplasm: P11388
• Total number of polymer chains: 3
• Total formula weight: 97478.31

Authors

Wendorff, T.J.,Schmidt, B.H.,Heslop, P.,Austin, C.A.,Berger, J.M. (deposition date: 2012-06-15, release date: 2012-08-08, Last modification date: 2024-02-28)

Primary citation

Wendorff, T.J.,Schmidt, B.H.,Heslop, P.,Austin, C.A.,Berger, J.M.
The Structure of DNA-Bound Human Topoisomerase II Alpha: Conformational Mechanisms for Coordinating Inter-Subunit Interactions with DNA Cleavage.
J.Mol.Biol., 424:109-124, 2012

PubMed Abstract: 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-Å-resolution structure of the DNA cleavage core of human topoisomerase IIα (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 IIβ (TOP2B) suggests possible modification points for developing paralog-specific inhibitors to overcome the tendency of topoisomerase II-targeting chemotherapeutics to generate secondary malignancies.

PubMed: 22841979
DOI: 10.1016/j.jmb.2012.07.014

Experimental method

X-RAY DIFFRACTION (2.901 Å)