View source for 7okc


==Crystal structure of Escherichia coli LpxA in complex with compound 1==
<StructureSection load='7okc' size='340' side='right'caption='[[7okc]], [[Resolution|resolution]] 1.84&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7okc]] 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=7OKC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7OKC 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]] 1.84&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=VFE:2-[2-(2-chlorophenyl)sulfanylethanoyl-[[4-(1,2,4-triazol-1-yl)phenyl]methyl]amino]-N-methyl-ethanamide'>VFE</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=7okc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7okc OCA], [https://pdbe.org/7okc PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7okc RCSB], [https://www.ebi.ac.uk/pdbsum/7okc PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7okc ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/C3TPH2_ECOLX C3TPH2_ECOLX] Involved in the biosynthesis of lipid A, a phosphorylated glycolipid that anchors the lipopolysaccharide to the outer membrane of the cell.[HAMAP-Rule:MF_00387]
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
This study describes a novel series of UDP-N-acetylglucosamine acyltransferase (LpxA) inhibitors that was identified through affinity-mediated selection from a DNA-encoded compound library. The original hit was a selective inhibitor of Pseudomonas aeruginosa LpxA with no activity against Escherichia coli LpxA. The biochemical potency of the series was optimized through an X-ray crystallography-supported medicinal chemistry program, resulting in compounds with nanomolar activity against P. aeruginosa LpxA (best half-maximal inhibitory concentration (IC50) &lt;5 nM) and cellular activity against P. aeruginosa (best minimal inhibitory concentration (MIC) of 4 mug/mL). Lack of activity against E. coli was maintained (IC50 &gt; 20 muM and MIC &gt; 128 mug/mL). The mode of action of analogues was confirmed through genetic analyses. As expected, compounds were active against multidrug-resistant isolates. Further optimization of pharmacokinetics is needed before efficacy studies in mouse infection models can be attempted. To our knowledge, this is the first reported LpxA inhibitor series with selective activity against P. aeruginosa.

Discovery of Novel UDP-N-Acetylglucosamine Acyltransferase (LpxA) Inhibitors with Activity against Pseudomonas aeruginosa.,Ryan MD, Parkes AL, Corbett D, Dickie AP, Southey M, Andersen OA, Stein DB, Barbeau OR, Sanzone A, Thommes P, Barker J, Cain R, Compper C, Dejob M, Dorali A, Etheridge D, Evans S, Faulkner A, Gadouleau E, Gorman T, Haase D, Holbrow-Wilshaw M, Krulle T, Li X, Lumley C, Mertins B, Napier S, Odedra R, Papadopoulos K, Roumpelakis V, Spear K, Trimby E, Williams J, Zahn M, Keefe AD, Zhang Y, Soutter HT, Centrella PA, Clark MA, Cuozzo JW, Dumelin CE, Deng B, Hunt A, Sigel EA, Troast DM, DeJonge BLM J Med Chem. 2021 Sep 27. doi: 10.1021/acs.jmedchem.1c00888. PMID:34569791<ref>PMID:34569791</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7okc" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Escherichia coli]]
[[Category: Large Structures]]
[[Category: Andersen OA]]
[[Category: Barker J]]
[[Category: DeJonge BLM]]
[[Category: Parkes AL]]
[[Category: Ryan MD]]
[[Category: Southey M]]
[[Category: Zahn M]]