View source for 7lhz


==K. pneumoniae Topoisomerase IV (ParE-ParC) in complex with DNA and (3S)-10-[(3R)-3-(1-aminocyclopropyl)pyrrolidin-1-yl]-9-fluoro-3-methyl-5-oxo-2,3-dihydro-5H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid (compound 25)==
<StructureSection load='7lhz' size='340' side='right'caption='[[7lhz]], [[Resolution|resolution]] 3.30&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7lhz]] 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=7LHZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7LHZ 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]] 3.3&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=MPD:(4S)-2-METHYL-2,4-PENTANEDIOL'>MPD</scene>, <scene name='pdbligand=Y21:(3S)-10-[(3R)-3-(1-aminocyclopropyl)pyrrolidin-1-yl]-9-fluoro-3-methyl-5-oxo-2,3-dihydro-5H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic+acid'>Y21</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=7lhz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7lhz OCA], [https://pdbe.org/7lhz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7lhz RCSB], [https://www.ebi.ac.uk/pdbsum/7lhz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7lhz ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/B5XU53_KLEP3 B5XU53_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_00938][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 ==
Herein, we describe the discovery and optimization of a novel series that inhibits bacterial DNA gyrase and topoisomerase IV via binding to, and stabilization of, DNA cleavage complexes. Optimization of this series led to the identification of compound 25, which has potent activity against Gram-positive bacteria, a favorable in vitro safety profile, and excellent in vivo pharmacokinetic properties. Compound 25 was found to be efficacious against fluoroquinolone-sensitive Staphylococcus aureus infection in a mouse thigh model at lower doses than moxifloxacin. An X-ray crystal structure of the ternary complex formed by topoisomerase IV from Klebsiella pneumoniae, compound 25, and cleaved DNA indicates that this compound does not engage in a water-metal ion bridge interaction and forms no direct contacts with residues in the quinolone resistance determining region (QRDR). This suggests a structural basis for the reduced impact of QRDR mutations on antibacterial activity of 25 compared to fluoroquinolones.

Discovery and Optimization of DNA Gyrase and Topoisomerase IV Inhibitors with Potent Activity against Fluoroquinolone-Resistant Gram-Positive Bacteria.,Lapointe G, Skepper CK, Holder LM, Armstrong D, Bellamacina C, Blais J, Bussiere D, Bian J, Cepura C, Chan H, Dean CR, De Pascale G, Dhumale B, Fisher LM, Fulsunder M, Kantariya B, Kim J, King S, Kossy L, Kulkarni U, Lakshman J, Leeds JA, Ling X, Lvov A, Ma S, Malekar S, McKenney D, Mergo W, Metzger L, Mhaske K, Moser HE, Mostafavi M, Namballa S, Noeske J, Osborne C, Patel A, Patel D, Patel T, Piechon P, Polyakov V, Prajapati K, Prosen KR, Reck F, Richie DL, Sanderson MR, Satasia S, Savani B, Selvarajah J, Sethuraman V, Shu W, Tashiro K, Thompson KV, Vaarla K, Vala L, Veselkov DA, Vo J, Vora B, Wagner T, Wedel L, Williams SL, Yendluri S, Yue Q, Yifru A, Zhang Y, Rivkin A J Med Chem. 2021 May 13;64(9):6329-6357. doi: 10.1021/acs.jmedchem.1c00375. Epub , 2021 Apr 30. PMID:33929852<ref>PMID:33929852</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7lhz" 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]]