View source for 7okb


==Crystal structure of Pseudomonas aeruginosa LpxA in complex with compound 45==
<StructureSection load='7okb' size='340' side='right'caption='[[7okb]], [[Resolution|resolution]] 3.58&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7okb]] is a 30 chain structure with sequence from [https://en.wikipedia.org/wiki/Pseudomonas_aeruginosa Pseudomonas aeruginosa]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7OKB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7OKB 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]] 3.58&#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=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=VFZ:~{N}-[(5-azanyl-1,3,4-oxadiazol-2-yl)methyl]-2-(2-chlorophenyl)sulfanyl-~{N}-[(6-oxidanylidene-1~{H}-pyridin-3-yl)methyl]ethanamide'>VFZ</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=7okb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7okb OCA], [https://pdbe.org/7okb PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7okb RCSB], [https://www.ebi.ac.uk/pdbsum/7okb PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7okb ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/A0A069Q726_PSEAI A0A069Q726_PSEAI] 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 7okb" style="background-color:#fffaf0;"></div>

==See Also==
*[[UDP-N-acetylglucosamine acyltransferase|UDP-N-acetylglucosamine acyltransferase]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Pseudomonas aeruginosa]]
[[Category: Andersen OA]]
[[Category: Barker J]]
[[Category: DeJonge BLM]]
[[Category: Parkes AL]]
[[Category: Ryan MD]]
[[Category: Southey M]]
[[Category: Zahn M]]