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==Crystal structure of E.coli DNA gyrase B in complex with 6-fluoro-8-(methylamino)-2-oxo-1,2-dihydroquinoline derivative== | ==Crystal structure of E.coli DNA gyrase B in complex with 6-fluoro-8-(methylamino)-2-oxo-1,2-dihydroquinoline derivative== | ||
<StructureSection load='7c7n' size='340' side='right'caption='[[7c7n]]' scene=''> | <StructureSection load='7c7n' size='340' side='right'caption='[[7c7n]], [[Resolution|resolution]] 2.30Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7C7N OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=7C7N FirstGlance]. <br> | <table><tr><td colspan='2'>[[7c7n]] 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=7C7N OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=7C7N FirstGlance]. <br> | ||
</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=7c7n FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7c7n OCA], [http://pdbe.org/7c7n PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=7c7n RCSB], [http://www.ebi.ac.uk/pdbsum/7c7n PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=7c7n ProSAT]</span></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FKR:4-[[6-fluoranyl-8-(methylamino)-2-oxidanylidene-1~{H}-quinolin-3-yl]carbonylamino]benzoic+acid'>FKR</scene></td></tr> | ||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">gyrB, NCTC10766_01911, NCTC9007_05029 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=562 "Bacillus coli" Migula 1895])</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'>[http://proteopedia.org/fgij/fg.htm?mol=7c7n FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7c7n OCA], [http://pdbe.org/7c7n PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=7c7n RCSB], [http://www.ebi.ac.uk/pdbsum/7c7n PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=7c7n ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Function == | |||
[[http://www.uniprot.org/uniprot/A0A210GCC1_ECOLX A0A210GCC1_ECOLX]] A type II topoisomerase that negatively supercoils closed circular double-stranded (ds) DNA in an ATP-dependent manner to modulate DNA topology and maintain chromosomes in an underwound state. Negative supercoiling favors strand separation, and DNA replication, transcription, recombination and repair, all of which involve strand separation. Also able to catalyze the interconversion of other topological isomers of dsDNA rings, including catenanes and knotted rings. Type II topoisomerases break and join 2 DNA strands simultaneously in an ATP-dependent manner.[HAMAP-Rule:MF_01898] | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The global increase in multidrug-resistant pathogens has caused severe problems in the treatment of infections. To overcome these difficulties, the advent of a new chemical class of antibacterial drug is eagerly desired. We aimed at creating novel antibacterial agents against bacterial type II topoisomerases, which are well-validated targets. TP0480066 (compound 32) has been identified by using structure-based optimization originated from lead compound 1, which was obtained as a result of our previous lead identification studies. The MIC90 values of TP0480066 against methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococci (VRE), and genotype penicillin-resistant Streptococcus pneumoniae (gPRSP) were 0.25, 0.015, and 0.06 mug/mL, respectively. Hence, TP0480066 can be regarded as a promising antibacterial drug candidate of this chemical class. | |||
Lead optimization of 8-(methylamino)-2-oxo-1,2-dihydroquinolines as bacterial type II topoisomerase inhibitors.,Ushiyama F, Amada H, Mihara Y, Takeuchi T, Tanaka-Yamamoto N, Mima M, Kamitani M, Wada R, Tamura Y, Endo M, Masuko A, Takata I, Hitaka K, Sugiyama H, Ohtake N Bioorg Med Chem. 2020 Sep 22;28(22):115776. doi: 10.1016/j.bmc.2020.115776. PMID:33032189<ref>PMID:33032189</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 7c7n" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Bacillus coli migula 1895]] | |||
[[Category: DNA topoisomerase]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Mima M]] | [[Category: Mima, M]] | ||
[[Category: Ushiyama F]] | [[Category: Ushiyama, F]] | ||
[[Category: Complex]] | |||
[[Category: Escherichia coli]] | |||
[[Category: Inhibitor]] | |||
[[Category: Isomerase]] | |||
[[Category: Topoisomerase]] | |||
Revision as of 11:44, 21 October 2020
Crystal structure of E.coli DNA gyrase B in complex with 6-fluoro-8-(methylamino)-2-oxo-1,2-dihydroquinoline derivativeCrystal structure of E.coli DNA gyrase B in complex with 6-fluoro-8-(methylamino)-2-oxo-1,2-dihydroquinoline derivative
Structural highlights
Function[A0A210GCC1_ECOLX] A type II topoisomerase that negatively supercoils closed circular double-stranded (ds) DNA in an ATP-dependent manner to modulate DNA topology and maintain chromosomes in an underwound state. Negative supercoiling favors strand separation, and DNA replication, transcription, recombination and repair, all of which involve strand separation. Also able to catalyze the interconversion of other topological isomers of dsDNA rings, including catenanes and knotted rings. Type II topoisomerases break and join 2 DNA strands simultaneously in an ATP-dependent manner.[HAMAP-Rule:MF_01898] Publication Abstract from PubMedThe global increase in multidrug-resistant pathogens has caused severe problems in the treatment of infections. To overcome these difficulties, the advent of a new chemical class of antibacterial drug is eagerly desired. We aimed at creating novel antibacterial agents against bacterial type II topoisomerases, which are well-validated targets. TP0480066 (compound 32) has been identified by using structure-based optimization originated from lead compound 1, which was obtained as a result of our previous lead identification studies. The MIC90 values of TP0480066 against methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococci (VRE), and genotype penicillin-resistant Streptococcus pneumoniae (gPRSP) were 0.25, 0.015, and 0.06 mug/mL, respectively. Hence, TP0480066 can be regarded as a promising antibacterial drug candidate of this chemical class. Lead optimization of 8-(methylamino)-2-oxo-1,2-dihydroquinolines as bacterial type II topoisomerase inhibitors.,Ushiyama F, Amada H, Mihara Y, Takeuchi T, Tanaka-Yamamoto N, Mima M, Kamitani M, Wada R, Tamura Y, Endo M, Masuko A, Takata I, Hitaka K, Sugiyama H, Ohtake N Bioorg Med Chem. 2020 Sep 22;28(22):115776. doi: 10.1016/j.bmc.2020.115776. PMID:33032189[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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