Document Detail


The structure of DNA-bound human topoisomerase II alpha: conformational mechanisms for coordinating inter-subunit interactions with DNA cleavage.
MedLine Citation:
PMID:  22841979     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Timothy J Wendorff; Bryan H Schmidt; Pauline Heslop; Caroline A Austin; James M Berger
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Publication Detail:
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:
Title:  Journal of molecular biology     Volume:  424     ISSN:  1089-8638     ISO Abbreviation:  J. Mol. Biol.     Publication Date:  2012 Dec 
Date Detail:
Created Date:  2012-11-12     Completed Date:  2013-01-29     Revised Date:  2013-12-12    
Medline Journal Info:
Nlm Unique ID:  2985088R     Medline TA:  J Mol Biol     Country:  England    
Other Details:
Languages:  eng     Pagination:  109-24     Citation Subset:  IM    
Copyright Information:
Copyright © 2012 Elsevier Ltd. All rights reserved.
Data Bank Information
Bank Name/Acc. No.:
PDB/4FM9
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MeSH Terms
Descriptor/Qualifier:
Antigens, Neoplasm / 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:
CA077373/CA/NCI NIH HHS; R01 CA077373/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
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:
J Mol Biol. 2012 Dec 7;424(3-4):105-8   [PMID:  23041421 ]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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