| The structure of DNA-bound human topoisomerase II alpha: conformational mechanisms for coordinating inter-subunit interactions with DNA cleavage. | |
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MedLine Citation:
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PMID: 22841979 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Timothy J Wendorff; Bryan H Schmidt; Pauline Heslop; Caroline A Austin; James M Berger |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S. Date: 2012-07-25 |
Journal Detail:
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Title: Journal of molecular biology Volume: 424 ISSN: 1089-8638 ISO Abbreviation: J. Mol. Biol. Publication Date: 2012 Dec |
Date Detail:
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Created Date: 2012-11-12 Completed Date: 2013-01-29 Revised Date: 2013-04-16 |
Medline Journal Info:
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Nlm Unique ID: 2985088R Medline TA: J Mol Biol Country: England |
Other Details:
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Languages: eng Pagination: 109-24 Citation Subset: IM |
Copyright Information:
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Copyright © 2012 Elsevier Ltd. All rights reserved. |
Affiliation:
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Biophysics Graduate Program, University of California Berkeley, Berkeley, CA 94720, USA. |
| Data Bank Information | |
Bank Name/Acc. No.:
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PDB/4FM9 |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Antigens, Neoplasm
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chemistry*,
metabolism Crystallography, X-Ray DNA / chemistry*, metabolism DNA Cleavage DNA Topoisomerases, Type II / chemistry*, metabolism DNA-Binding Proteins / chemistry*, metabolism Humans Models, Molecular Protein Binding Protein Conformation Protein Subunits / chemistry, metabolism |
| Grant Support | |
ID/Acronym/Agency:
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CA077373/CA/NCI NIH HHS; R01 CA077373/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Antigens, Neoplasm; 0/DNA-Binding Proteins; 0/Protein Subunits; 9007-49-2/DNA; EC 5.99.1.3/DNA Topoisomerases, Type II; EC 5.99.1.3/DNA topoisomerase II alpha |
| Comments/Corrections | |
Comment In:
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J Mol Biol. 2012 Dec 7;424(3-4):105-8
[PMID:
23041421
]
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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