6l01: Difference between revisions
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==Crystal structure of E.coli DNA gyrase B in complex with 2-oxo-1,2-dihydroquinoline derivative== | |||
<StructureSection load='6l01' size='340' side='right'caption='[[6l01]], [[Resolution|resolution]] 2.60Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6l01]] 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=6L01 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6L01 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]] 2.6Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=E0U:2-[3-[[8-(methylamino)-2-oxidanylidene-1~{H}-quinolin-3-yl]carbonylamino]phenyl]ethanoic+acid'>E0U</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=6l01 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6l01 OCA], [https://pdbe.org/6l01 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6l01 RCSB], [https://www.ebi.ac.uk/pdbsum/6l01 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6l01 ProSAT]</span></td></tr> | |||
</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;"> | |||
== 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<ref>PMID:32391502</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: Mima | <div class="pdbe-citations 6l01" style="background-color:#fffaf0;"></div> | ||
==See Also== | |||
*[[Gyrase 3D Structures|Gyrase 3D Structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Escherichia coli]] | |||
[[Category: Large Structures]] | |||
[[Category: Mima M]] | |||
[[Category: Takeuchi T]] | |||
[[Category: Ushiyama F]] | |||
Latest revision as of 13:47, 22 November 2023
Crystal structure of E.coli DNA gyrase B in complex with 2-oxo-1,2-dihydroquinoline derivativeCrystal structure of E.coli DNA gyrase B in complex with 2-oxo-1,2-dihydroquinoline derivative
Structural highlights
FunctionGYRB_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 PubMedDNA 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 AlsoReferences
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