2xct: Difference between revisions
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< | ==The twinned 3.35A structure of S. aureus Gyrase complex with Ciprofloxacin and DNA== | ||
<StructureSection load='2xct' size='340' side='right'caption='[[2xct]], [[Resolution|resolution]] 3.35Å' scene=''> | |||
You may | == Structural highlights == | ||
<table><tr><td colspan='2'>[[2xct]] is a 12 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=2XCT OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2XCT FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.35Å</td></tr> | |||
- | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CPF:1-CYCLOPROPYL-6-FLUORO-4-OXO-7-PIPERAZIN-1-YL-1,4-DIHYDROQUINOLINE-3-CARBOXYLIC+ACID'>CPF</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene></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=2xct FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2xct OCA], [https://pdbe.org/2xct PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2xct RCSB], [https://www.ebi.ac.uk/pdbsum/2xct PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2xct ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[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][https://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). | |||
== Evolutionary Conservation == | |||
[[Image:Consurf_key_small.gif|200px|right]] | |||
Check<jmol> | |||
<jmolCheckbox> | |||
<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/xc/2xct_consurf.spt"</scriptWhenChecked> | |||
<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> | |||
<text>to colour the structure by Evolutionary Conservation</text> | |||
</jmolCheckbox> | |||
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2xct ConSurf]. | |||
<div style="clear:both"></div> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Despite the success of genomics in identifying new essential bacterial genes, there is a lack of sustainable leads in antibacterial drug discovery to address increasing multidrug resistance. Type IIA topoisomerases cleave and religate DNA to regulate DNA topology and are a major class of antibacterial and anticancer drug targets, yet there is no well developed structural basis for understanding drug action. Here we report the 2.1 A crystal structure of a potent, new class, broad-spectrum antibacterial agent in complex with Staphylococcus aureus DNA gyrase and DNA, showing a new mode of inhibition that circumvents fluoroquinolone resistance in this clinically important drug target. The inhibitor 'bridges' the DNA and a transient non-catalytic pocket on the two-fold axis at the GyrA dimer interface, and is close to the active sites and fluoroquinolone binding sites. In the inhibitor complex the active site seems poised to cleave the DNA, with a single metal ion observed between the TOPRIM (topoisomerase/primase) domain and the scissile phosphate. This work provides new insights into the mechanism of topoisomerase action and a platform for structure-based drug design of a new class of antibacterial agents against a clinically proven, but conformationally flexible, enzyme class. | |||
Type IIA topoisomerase inhibition by a new class of antibacterial agents.,Bax BD, Chan PF, Eggleston DS, Fosberry A, Gentry DR, Gorrec F, Giordano I, Hann MM, Hennessy A, Hibbs M, Huang J, Jones E, Jones J, Brown KK, Lewis CJ, May EW, Saunders MR, Singh O, Spitzfaden CE, Shen C, Shillings A, Theobald AJ, Wohlkonig A, Pearson ND, Gwynn MN Nature. 2010 Aug 19;466(7309):935-40. Epub 2010 Aug 4. PMID:20686482<ref>PMID:20686482</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 2xct" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Gyrase 3D Structures|Gyrase 3D Structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
== | [[Category: Large Structures]] | ||
[[Category: Staphylococcus aureus subsp. aureus N315]] | |||
[[Category: Synthetic construct]] | |||
== | [[Category: Bax BD]] | ||
< | [[Category: Brown KK]] | ||
[[Category: Staphylococcus aureus]] | [[Category: Chan P]] | ||
[[Category: Bax | [[Category: Eggleston DS]] | ||
[[Category: Brown | [[Category: Fosberry A]] | ||
[[Category: Chan | [[Category: Gentry DR]] | ||
[[Category: Eggleston | [[Category: Giordano I]] | ||
[[Category: Fosberry | [[Category: Gorrec F]] | ||
[[Category: Gentry | [[Category: Gwynn MN]] | ||
[[Category: Giordano | [[Category: Hann MM]] | ||
[[Category: Gorrec | [[Category: Hennessy A]] | ||
[[Category: Gwynn | [[Category: Hibbs M]] | ||
[[Category: Hann | [[Category: Huang J]] | ||
[[Category: Hennessy | [[Category: Jones E]] | ||
[[Category: Hibbs | [[Category: Jones J]] | ||
[[Category: Huang | [[Category: Lewis CJ]] | ||
[[Category: Jones | [[Category: May E]] | ||
[[Category: Jones | [[Category: Pearson ND]] | ||
[[Category: Lewis | [[Category: Shen C]] | ||
[[Category: May | [[Category: Shillings A]] | ||
[[Category: Pearson | [[Category: Singh O]] | ||
[[Category: Shen | [[Category: Spitzfaden C]] | ||
[[Category: Shillings | [[Category: Theobald A]] | ||
[[Category: Singh | [[Category: Wohlkonig A]] | ||
[[Category: Spitzfaden | |||
[[Category: Theobald | |||
[[Category: Wohlkonig | |||
Latest revision as of 13:24, 9 May 2024
The twinned 3.35A structure of S. aureus Gyrase complex with Ciprofloxacin and DNAThe twinned 3.35A structure of S. aureus Gyrase complex with Ciprofloxacin and DNA
Structural highlights
FunctionGYRA_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]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). Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedDespite the success of genomics in identifying new essential bacterial genes, there is a lack of sustainable leads in antibacterial drug discovery to address increasing multidrug resistance. Type IIA topoisomerases cleave and religate DNA to regulate DNA topology and are a major class of antibacterial and anticancer drug targets, yet there is no well developed structural basis for understanding drug action. Here we report the 2.1 A crystal structure of a potent, new class, broad-spectrum antibacterial agent in complex with Staphylococcus aureus DNA gyrase and DNA, showing a new mode of inhibition that circumvents fluoroquinolone resistance in this clinically important drug target. The inhibitor 'bridges' the DNA and a transient non-catalytic pocket on the two-fold axis at the GyrA dimer interface, and is close to the active sites and fluoroquinolone binding sites. In the inhibitor complex the active site seems poised to cleave the DNA, with a single metal ion observed between the TOPRIM (topoisomerase/primase) domain and the scissile phosphate. This work provides new insights into the mechanism of topoisomerase action and a platform for structure-based drug design of a new class of antibacterial agents against a clinically proven, but conformationally flexible, enzyme class. Type IIA topoisomerase inhibition by a new class of antibacterial agents.,Bax BD, Chan PF, Eggleston DS, Fosberry A, Gentry DR, Gorrec F, Giordano I, Hann MM, Hennessy A, Hibbs M, Huang J, Jones E, Jones J, Brown KK, Lewis CJ, May EW, Saunders MR, Singh O, Spitzfaden CE, Shen C, Shillings A, Theobald AJ, Wohlkonig A, Pearson ND, Gwynn MN Nature. 2010 Aug 19;466(7309):935-40. Epub 2010 Aug 4. PMID:20686482[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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