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| | <StructureSection load='6kzv' size='340' side='right'caption='[[6kzv]], [[Resolution|resolution]] 2.40Å' scene=''> | | <StructureSection load='6kzv' size='340' side='right'caption='[[6kzv]], [[Resolution|resolution]] 2.40Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6kzv]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/"bacillus_coli"_migula_1895 "bacillus coli" migula 1895]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6KZV OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6KZV FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6kzv]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Escherichia_coli Escherichia coli]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6KZV OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6KZV FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=E0F:~{N}-[2-[[cyclohexyl(methyl)amino]methyl]phenyl]-2-oxidanylidene-1~{H}-quinoline-3-carboxamide'>E0F</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.4Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">gyrB, C9Z04_12785 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=562 "Bacillus coli" Migula 1895])</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=E0F:~{N}-[2-[[cyclohexyl(methyl)amino]methyl]phenyl]-2-oxidanylidene-1~{H}-quinoline-3-carboxamide'>E0F</scene></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 DNA topoisomerase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=5.6.2.2 5.6.2.2] </span></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=6kzv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6kzv OCA], [https://pdbe.org/6kzv PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6kzv RCSB], [https://www.ebi.ac.uk/pdbsum/6kzv PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6kzv ProSAT]</span></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6kzv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6kzv OCA], [http://pdbe.org/6kzv PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6kzv RCSB], [http://www.ebi.ac.uk/pdbsum/6kzv PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6kzv ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/GYRB_ECOLI GYRB_ECOLI] 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.<ref>PMID:12051843</ref> <ref>PMID:18642932</ref> <ref>PMID:20675723</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 6kzv" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 6kzv" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Gyrase 3D Structures|Gyrase 3D Structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Bacillus coli migula 1895]] | |
| - | [[Category: DNA topoisomerase]] | |
| - | [[Category: Large Structures]] | |
| - | [[Category: Mima, M]] | |
| - | [[Category: Ushiyama, F]] | |
| - | [[Category: Complex]] | |
| | [[Category: Escherichia coli]] | | [[Category: Escherichia coli]] |
| - | [[Category: Inhibitor]] | + | [[Category: Large Structures]] |
| - | [[Category: Isomerase]] | + | [[Category: Mima M]] |
| - | [[Category: Topoisomerase]] | + | [[Category: Ushiyama F]] |
| Structural highlights
Function
GYRB_ECOLI 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.[1] [2] [3]
Publication Abstract from PubMed
DNA gyrase and topoisomerase IV are well-validated pharmacological targets, and quinolone antibacterial drugs are marketed as their representative inhibitors. However, in recent years, resistance to these existing drugs has become a problem, and new chemical classes of antibiotics that can combat resistant strains of bacteria are strongly needed. In this study, we applied our hit-to-lead (H2L) chemistry for the identification of a new chemical class of GyrB/ParE inhibitors by efficient use of thermodynamic parameters. Investigation of the core fragments obtained by fragmentation of high-throughput screening hit compounds and subsequent expansion of the hit fragment was performed using isothermal titration calorimetry (ITC). The 8-(methylamino)-2-oxo-1,2-dihydroquinoline derivative 13e showed potent activity against Escherichia coli DNA gyrase with an IC50 value of 0.0017 muM. In this study, we demonstrated the use of ITC for primary fragment screening, followed by structural optimization to obtain lead compounds, which advanced into further optimization for creating novel antibacterial agents.
Lead Identification of 8-(Methylamino)-2-oxo-1,2-dihydroquinoline Derivatives as DNA Gyrase Inhibitors: Hit-to-Lead Generation Involving Thermodynamic Evaluation.,Ushiyama F, Amada H, Takeuchi T, Tanaka-Yamamoto N, Kanazawa H, Nakano K, Mima M, Masuko A, Takata I, Hitaka K, Iwamoto K, Sugiyama H, Ohtake N ACS Omega. 2020 Apr 24;5(17):10145-10159. doi: 10.1021/acsomega.0c00865., eCollection 2020 May 5. PMID:32391502[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Noble CG, Maxwell A. The role of GyrB in the DNA cleavage-religation reaction of DNA gyrase: a proposed two metal-ion mechanism. J Mol Biol. 2002 Apr 26;318(2):361-71. PMID:12051843 doi:http://dx.doi.org/10.1016/S0022-2836(02)00049-9
- ↑ Sissi C, Chemello A, Vazquez E, Mitchenall LA, Maxwell A, Palumbo M. DNA gyrase requires DNA for effective two-site coordination of divalent metal ions: further insight into the mechanism of enzyme action. Biochemistry. 2008 Aug 19;47(33):8538-45. doi: 10.1021/bi800480j. Epub 2008 Jul, 22. PMID:18642932 doi:http://dx.doi.org/10.1021/bi800480j
- ↑ Schoeffler AJ, May AP, Berger JM. A domain insertion in Escherichia coli GyrB adopts a novel fold that plays a critical role in gyrase function. Nucleic Acids Res. 2010 Jul 31. PMID:20675723 doi:10.1093/nar/gkq665
- ↑ Ushiyama F, Amada H, Takeuchi T, Tanaka-Yamamoto N, Kanazawa H, Nakano K, Mima M, Masuko A, Takata I, Hitaka K, Iwamoto K, Sugiyama H, Ohtake N. Lead Identification of 8-(Methylamino)-2-oxo-1,2-dihydroquinoline Derivatives as DNA Gyrase Inhibitors: Hit-to-Lead Generation Involving Thermodynamic Evaluation. ACS Omega. 2020 Apr 24;5(17):10145-10159. doi: 10.1021/acsomega.0c00865., eCollection 2020 May 5. PMID:32391502 doi:http://dx.doi.org/10.1021/acsomega.0c00865
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