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| | <StructureSection load='5cdp' size='340' side='right'caption='[[5cdp]], [[Resolution|resolution]] 2.45Å' scene=''> | | <StructureSection load='5cdp' size='340' side='right'caption='[[5cdp]], [[Resolution|resolution]] 2.45Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5cdp]] is a 8 chain structure with sequence from [http://en.wikipedia.org/wiki/Staan Staan]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5CDP OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5CDP FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5cdp]] is a 8 chain structure with sequence from [https://en.wikipedia.org/wiki/Staphylococcus_aureus_subsp._aureus_N315 Staphylococcus aureus subsp. aureus N315] 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=5CDP OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5CDP FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EVP:(5S,5AR,8AR,9R)-9-(4-HYDROXY-3,5-DIMETHOXYPHENYL)-8-OXO-5,5A,6,8,8A,9-HEXAHYDROFURO[3,4 6,7]NAPHTHO[2,3-D][1,3]DIOXOL-5-YL+4,6-O-[(1R)-ETHYLIDENE]-BETA-D-GLUCOPYRANOSIDE'>EVP</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EVP:(5S,5AR,8AR,9R)-9-(4-HYDROXY-3,5-DIMETHOXYPHENYL)-8-OXO-5,5A,6,8,8A,9-HEXAHYDROFURO[3,4 6,7]NAPHTHO[2,3-D][1,3]DIOXOL-5-YL+4,6-O-[(1R)-ETHYLIDENE]-BETA-D-GLUCOPYRANOSIDE'>EVP</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">gyrA, SA0006 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=158879 STAAN]), gyrB, SA0005 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=158879 STAAN])</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=5cdp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5cdp OCA], [https://pdbe.org/5cdp PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5cdp RCSB], [https://www.ebi.ac.uk/pdbsum/5cdp PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5cdp 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=5cdp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5cdp OCA], [http://pdbe.org/5cdp PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5cdp RCSB], [http://www.ebi.ac.uk/pdbsum/5cdp PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5cdp ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/GYRA_STAAN GYRA_STAAN]] DNA gyrase negatively supercoils closed circular double-stranded DNA in an ATP-dependent manner and also catalyzes the interconversion of other topological isomers of double-stranded DNA rings, including catenanes and knotted rings.[HAMAP-Rule:MF_01897] [[http://www.uniprot.org/uniprot/GYRB_STAAN GYRB_STAAN]] DNA gyrase negatively supercoils closed circular double-stranded DNA in an ATP-dependent manner and also catalyzes the interconversion of other topological isomers of double-stranded DNA rings, including catenanes and knotted rings (By similarity). | + | [https://www.uniprot.org/uniprot/GYRA_STAAN GYRA_STAAN] DNA gyrase negatively supercoils closed circular double-stranded DNA in an ATP-dependent manner and also catalyzes the interconversion of other topological isomers of double-stranded DNA rings, including catenanes and knotted rings.[HAMAP-Rule:MF_01897] |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </StructureSection> | | </StructureSection> |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Staan]] | + | [[Category: Staphylococcus aureus subsp. aureus N315]] |
| - | [[Category: Bax, B D]] | + | [[Category: Synthetic construct]] |
| - | [[Category: Chan, P F]] | + | [[Category: Bax BD]] |
| - | [[Category: Srikannathasan, V]] | + | [[Category: Chan PF]] |
| - | [[Category: Antibacterial]] | + | [[Category: Srikannathasan V]] |
| - | [[Category: Fusion protein]]
| + | |
| - | [[Category: Inhibitor]]
| + | |
| - | [[Category: Isomerase]]
| + | |
| - | [[Category: Type iia topoisomerase]]
| + | |
| Structural highlights
Function
GYRA_STAAN DNA gyrase negatively supercoils closed circular double-stranded DNA in an ATP-dependent manner and also catalyzes the interconversion of other topological isomers of double-stranded DNA rings, including catenanes and knotted rings.[HAMAP-Rule:MF_01897]
Publication Abstract from PubMed
New antibacterials are needed to tackle antibiotic-resistant bacteria. Type IIA topoisomerases (topo2As), the targets of fluoroquinolones, regulate DNA topology by creating transient double-strand DNA breaks. Here we report the first co-crystal structures of the antibacterial QPT-1 and the anticancer drug etoposide with Staphylococcus aureus DNA gyrase, showing binding at the same sites in the cleaved DNA as the fluoroquinolone moxifloxacin. Unlike moxifloxacin, QPT-1 and etoposide interact with conserved GyrB TOPRIM residues rationalizing why QPT-1 can overcome fluoroquinolone resistance. Our data show etoposide's antibacterial activity is due to DNA gyrase inhibition and suggests other anticancer agents act similarly. Analysis of multiple DNA gyrase co-crystal structures, including asymmetric cleavage complexes, led to a 'pair of swing-doors' hypothesis in which the movement of one DNA segment regulates cleavage and religation of the second DNA duplex. This mechanism can explain QPT-1's bacterial specificity. Structure-based strategies for developing topo2A antibacterials are suggested.
Structural basis of DNA gyrase inhibition by antibacterial QPT-1, anticancer drug etoposide and moxifloxacin.,Chan PF, Srikannathasan V, Huang J, Cui H, Fosberry AP, Gu M, Hann MM, Hibbs M, Homes P, Ingraham K, Pizzollo J, Shen C, Shillings AJ, Spitzfaden CE, Tanner R, Theobald AJ, Stavenger RA, Bax BD, Gwynn MN Nat Commun. 2015 Dec 7;6:10048. doi: 10.1038/ncomms10048. PMID:26640131[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Chan PF, Srikannathasan V, Huang J, Cui H, Fosberry AP, Gu M, Hann MM, Hibbs M, Homes P, Ingraham K, Pizzollo J, Shen C, Shillings AJ, Spitzfaden CE, Tanner R, Theobald AJ, Stavenger RA, Bax BD, Gwynn MN. Structural basis of DNA gyrase inhibition by antibacterial QPT-1, anticancer drug etoposide and moxifloxacin. Nat Commun. 2015 Dec 7;6:10048. doi: 10.1038/ncomms10048. PMID:26640131 doi:http://dx.doi.org/10.1038/ncomms10048
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