View source for 4plb


==Crystal Structure of S.A. gyrase-AM8191 complex==
<StructureSection load='4plb' size='340' side='right'caption='[[4plb]], [[Resolution|resolution]] 2.69&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4plb]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Staphylococcus_aureus Staphylococcus aureus] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4PLB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4PLB 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]] 2.69&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=31N:6-[({(1R,4S)-1-[(1S)-2-(3-FLUORO-6-METHOXY-1,5-NAPHTHYRIDIN-4-YL)-1-HYDROXYETHYL]-2-OXABICYCLO[2.2.2]OCT-4-YL}AMINO)METHYL]-2H-PYRIDO[3,2-B][1,4]OXAZIN-3(4H)-ONE'>31N</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=4plb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4plb OCA], [https://pdbe.org/4plb PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4plb RCSB], [https://www.ebi.ac.uk/pdbsum/4plb PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4plb ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/GYRB_STAAU GYRB_STAAU] 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.[HAMAP-Rule:MF_01898][https://www.uniprot.org/uniprot/GYRA_STAAU GYRA_STAAU] 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_01897]
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Bacterial resistance is eroding the clinical utility of existing antibiotics necessitating the discovery of new agents. Bacterial type II topoisomerase is a clinically validated, highly effective, and proven drug target. This target is amenable to inhibition by diverse classes of inhibitors with alternative and distinct binding sites to quinolone antibiotics, thus enabling the development of agents that lack cross-resistance to quinolones. Described here are novel bacterial topoisomerase inhibitors (NBTIs), which are a new class of gyrase and topo IV inhibitors and consist of three distinct structural moieties. The substitution of the linker moiety led to discovery of potent broad-spectrum NBTIs with reduced off-target activity (hERG IC50 &gt; 18 muM) and improved physical properties. AM8191 is bactericidal and selectively inhibits DNA synthesis and Staphylococcus aureus gyrase (IC50 = 1.02 muM) and topo IV (IC50 = 10.4 muM). AM8191 showed parenteral and oral efficacy (ED50) at less than 2.5 mg/kg doses in a S. aureus murine infection model. A cocrystal structure of AM8191 bound to S. aureus DNA-gyrase showed binding interactions similar to that reported for GSK299423, displaying a key contact of Asp83 with the basic amine at position-7 of the linker.

Oxabicyclooctane-linked novel bacterial topoisomerase inhibitors as broad spectrum antibacterial agents.,Singh SB, Kaelin DE, Wu J, Miesel L, Tan CM, Meinke PT, Olsen D, Lagrutta A, Bradley P, Lu J, Patel S, Rickert KW, Smith RF, Soisson S, Wei C, Fukuda H, Kishii R, Takei M, Fukuda Y ACS Med Chem Lett. 2014 Mar 12;5(5):609-14. doi: 10.1021/ml500069w. eCollection, 2014 May 8. PMID:24900889<ref>PMID:24900889</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4plb" style="background-color:#fffaf0;"></div>

==See Also==
*[[Gyrase|Gyrase]]
*[[Gyrase 3D Structures|Gyrase 3D Structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Staphylococcus aureus]]
[[Category: Synthetic construct]]
[[Category: Lu J]]
[[Category: Patel S]]
[[Category: Soisson S]]