View source for 5mmo


==E. coli DNA Gyrase B 24 kDa ATPase domain in complex with [3-(3-ethyl-ureido)-5-(pyridin-4-yl)-isoquinolin-8-yl-methyl]-carbamic acid prop-2-ynyl ester==
<StructureSection load='5mmo' size='340' side='right'caption='[[5mmo]], [[Resolution|resolution]] 1.81&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5mmo]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Escherichia_coli_O157:H7 Escherichia coli O157:H7]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5MMO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5MMO 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]] 1.81&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=9JG:PROP-2-YNYL+~{N}-[[3-(ETHYLCARBAMOYLAMINO)-5-PYRIDIN-4-YL-ISOQUINOLIN-8-YL]METHYL]CARBAMATE'>9JG</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</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=5mmo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5mmo OCA], [https://pdbe.org/5mmo PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5mmo RCSB], [https://www.ebi.ac.uk/pdbsum/5mmo PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5mmo ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/GYRB_ECO57 GYRB_ECO57] 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]
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Our strategy to combat resistant bacteria consisted of targeting the GyrB/ParE ATP-binding sites located on bacterial DNA gyrase and topoisomerase IV and not utilized by marketed antibiotics. Screening around the minimal ethyl urea binding motif led to the identification of isoquinoline ethyl urea 13 as a promising starting point for fragment evolution. The optimization was guided by structure-based design and focused on antibacterial activity in vitro and in vivo, culminating in the discovery of unprecedented substituents able to interact with conserved residues within the ATP-binding site. A detailed characterization of the lead compound highlighted the potential for treatment of the problematic fluoroquinolone-resistant MRSA, VRE, and S. pneumoniae, and the possibility to offer patients an intravenous-to-oral switch therapy was supported by the identification of a suitable prodrug concept. Eventually, hERG K-channel block was identified as the main limitation of this chemical series, and efforts toward its minimization are reported.

Discovery and Optimization of Isoquinoline Ethyl Ureas as Antibacterial Agents.,Panchaud P, Bruyere T, Blumstein AC, Bur D, Chambovey A, Ertel EA, Gude M, Hubschwerlen C, Jacob L, Kimmerlin T, Pfeifer T, Prade L, Seiler P, Ritz D, Rueedi G J Med Chem. 2017 Apr 24. doi: 10.1021/acs.jmedchem.6b01834. PMID:28406299<ref>PMID:28406299</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 5mmo" style="background-color:#fffaf0;"></div>

==See Also==
*[[Gyrase 3D Structures|Gyrase 3D Structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Escherichia coli O157:H7]]
[[Category: Large Structures]]
[[Category: Blumstein A-C]]
[[Category: Bruyere T]]
[[Category: Bur D]]
[[Category: Chambovey A]]
[[Category: Ertel EA]]
[[Category: Gude M]]
[[Category: Hubschwerlen C]]
[[Category: Jacob L]]
[[Category: Kimmerlin T]]
[[Category: Panchaud P]]
[[Category: Pfeifer T]]
[[Category: Prade L]]
[[Category: Ritz D]]
[[Category: Rueedi G]]
[[Category: Seiler P]]