View source for 6waa


==K. pneumoniae Topoisomerase IV (ParE-ParC) in complex with DNA and compound 34 (7-[(1S,5R)-1-amino-3-azabicyclo[3.1.0]hexan-3-yl]-4-(aminomethyl)-1-cyclopropyl-3,6-difluoro-8-methylquinolin-2(1H)-one)==
<StructureSection load='6waa' size='340' side='right'caption='[[6waa]], [[Resolution|resolution]] 3.20&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6waa]] is a 12 chain structure with sequence from [https://en.wikipedia.org/wiki/Klebsiella_pneumoniae_342 Klebsiella pneumoniae 342]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6WAA OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6WAA 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]] 3.2&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=MPD:(4S)-2-METHYL-2,4-PENTANEDIOL'>MPD</scene>, <scene name='pdbligand=PTR:O-PHOSPHOTYROSINE'>PTR</scene>, <scene name='pdbligand=TNJ:7-[(1S,5R)-1-amino-3-azabicyclo[3.1.0]hexan-3-yl]-4-(aminomethyl)-1-cyclopropyl-3,6-difluoro-8-methylquinolin-2(1H)-one'>TNJ</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=6waa FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6waa OCA], [https://pdbe.org/6waa PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6waa RCSB], [https://www.ebi.ac.uk/pdbsum/6waa PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6waa ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/B5XU60_KLEP3 B5XU60_KLEP3] Topoisomerase IV is essential for chromosome segregation. It relaxes supercoiled DNA. Performs the decatenation events required during the replication of a circular DNA molecule.[HAMAP-Rule:MF_00936]
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Since their discovery over 5 decades ago, quinolone antibiotics have found enormous success as broad spectrum agents that exert their activity through dual inhibition of bacterial DNA gyrase and topoisomerase IV. Increasing rates of resistance, driven largely by target-based mutations in the GyrA/ParC quinolone resistance determining region, have eroded the utility and threaten the future use of this vital class of antibiotics. Herein we describe the discovery and optimization of a series of 4-(aminomethyl)quinolin-2(1H)-ones, exemplified by 34, that inhibit bacterial DNA gyrase and topoisomerase IV and display potent activity against ciprofloxacin-resistant Gram-negative pathogens. X-ray crystallography reveals that 34 occupies the classical quinolone binding site in the topoisomerase IV-DNA cleavage complex but does not form significant contacts with residues in the quinolone resistance determining region.

Topoisomerase Inhibitors Addressing Fluoroquinolone Resistance in Gram-Negative Bacteria.,Skepper CK, Armstrong D, Balibar CJ, Bauer D, Bellamacina C, Benton BM, Bussiere D, De Pascale G, De Vicente J, Dean CR, Dhumale B, Fisher LM, Fuller J, Fulsunder M, Holder LM, Hu C, Kantariya B, Lapointe G, Leeds JA, Li X, Lu P, Lvov A, Ma S, Madhavan S, Malekar S, McKenney D, Mergo W, Metzger L, Moser HE, Mutnick D, Noeske J, Osborne C, Patel A, Patel D, Patel T, Prajapati K, Prosen KR, Reck F, Richie DL, Rico A, Sanderson MR, Satasia S, Sawyer WS, Selvarajah J, Shah N, Shanghavi K, Shu W, Thompson KV, Traebert M, Vala A, Vala L, Veselkov DA, Vo J, Wang M, Widya M, Williams SL, Xu Y, Yue Q, Zang R, Zhou B, Rivkin A J Med Chem. 2020 Jul 23;63(14):7773-7816. doi: 10.1021/acs.jmedchem.0c00347. Epub, 2020 Jul 7. PMID:32634310<ref>PMID:32634310</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6waa" style="background-color:#fffaf0;"></div>

==See Also==
*[[Topoisomerase 3D structures|Topoisomerase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Klebsiella pneumoniae 342]]
[[Category: Large Structures]]
[[Category: Bellamacina C]]
[[Category: Noeske J]]
[[Category: Shu W]]