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| | ==Human topoisomerase II alpha bound to DNA== | | ==Human topoisomerase II alpha bound to DNA== |
| - | <StructureSection load='4fm9' size='340' side='right' caption='[[4fm9]], [[Resolution|resolution]] 2.90Å' scene=''> | + | <StructureSection load='4fm9' size='340' side='right'caption='[[4fm9]], [[Resolution|resolution]] 2.90Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4fm9]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4FM9 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4FM9 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4fm9]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4FM9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4FM9 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">TOP2, TOP2A ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4fm9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4fm9 OCA], [https://pdbe.org/4fm9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4fm9 RCSB], [https://www.ebi.ac.uk/pdbsum/4fm9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4fm9 ProSAT]</span></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/DNA_topoisomerase_(ATP-hydrolyzing) DNA topoisomerase (ATP-hydrolyzing)], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=5.99.1.3 5.99.1.3] </span></td></tr>
| + | |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4fm9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4fm9 OCA], [http://pdbe.org/4fm9 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4fm9 RCSB], [http://www.ebi.ac.uk/pdbsum/4fm9 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4fm9 ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/TOP2A_HUMAN TOP2A_HUMAN]] Control of topological states of DNA by transient breakage and subsequent rejoining of DNA strands. Topoisomerase II makes double-strand breaks. Essential during mitosis and meiosis for proper segregation of daughter chromosomes.<ref>PMID:22323612</ref> | + | [https://www.uniprot.org/uniprot/TOP2A_HUMAN TOP2A_HUMAN] Control of topological states of DNA by transient breakage and subsequent rejoining of DNA strands. Topoisomerase II makes double-strand breaks. Essential during mitosis and meiosis for proper segregation of daughter chromosomes.<ref>PMID:22323612</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | ==See Also== | | ==See Also== |
| - | *[[Topoisomerase|Topoisomerase]] | + | *[[Topoisomerase 3D structures|Topoisomerase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Austin, C A]] | + | [[Category: Large Structures]] |
| - | [[Category: Berger, J M]] | + | [[Category: Synthetic construct]] |
| - | [[Category: Heslop, P]] | + | [[Category: Austin CA]] |
| - | [[Category: Schmidt, B H]] | + | [[Category: Berger JM]] |
| - | [[Category: Wendorff, T J]] | + | [[Category: Heslop P]] |
| - | [[Category: Dna-binding]] | + | [[Category: Schmidt BH]] |
| - | [[Category: Isomerase-dna complex]] | + | [[Category: Wendorff TJ]] |
| - | [[Category: Protein-dna complex]]
| + | |
| - | [[Category: Topoisomerase]]
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| Structural highlights
Function
TOP2A_HUMAN Control of topological states of DNA by transient breakage and subsequent rejoining of DNA strands. Topoisomerase II makes double-strand breaks. Essential during mitosis and meiosis for proper segregation of daughter chromosomes.[1]
Publication Abstract from PubMed
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-A-resolution structure of the DNA cleavage core of human topoisomerase IIalpha (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 IIbeta (TOP2B) suggests possible modification points for developing paralog-specific inhibitors to overcome the tendency of topoisomerase II-targeting chemotherapeutics to generate secondary malignancies.
The Structure of DNA-Bound Human Topoisomerase II Alpha: Conformational Mechanisms for Coordinating Inter-Subunit Interactions with DNA Cleavage.,Wendorff TJ, Schmidt BH, Heslop P, Austin CA, Berger JM J Mol Biol. 2012 Dec 7;424(3-4):109-24. doi: 10.1016/j.jmb.2012.07.014. Epub 2012, Jul 25. PMID:22841979[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Lee S, Jung SR, Heo K, Byl JA, Deweese JE, Osheroff N, Hohng S. DNA cleavage and opening reactions of human topoisomerase IIalpha are regulated via Mg2+-mediated dynamic bending of gate-DNA. Proc Natl Acad Sci U S A. 2012 Feb 21;109(8):2925-30. doi:, 10.1073/pnas.1115704109. Epub 2012 Feb 9. PMID:22323612 doi:http://dx.doi.org/10.1073/pnas.1115704109
- ↑ Wendorff TJ, Schmidt BH, Heslop P, Austin CA, Berger JM. The Structure of DNA-Bound Human Topoisomerase II Alpha: Conformational Mechanisms for Coordinating Inter-Subunit Interactions with DNA Cleavage. J Mol Biol. 2012 Dec 7;424(3-4):109-24. doi: 10.1016/j.jmb.2012.07.014. Epub 2012, Jul 25. PMID:22841979 doi:http://dx.doi.org/10.1016/j.jmb.2012.07.014
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