View source for 7cic


==Crystal structure of P.aeruginosa LpxC in complex with inhibitor==
<StructureSection load='7cic' size='340' side='right'caption='[[7cic]], [[Resolution|resolution]] 1.78&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7cic]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Pseudomonas_aeruginosa_PAO1 Pseudomonas aeruginosa PAO1]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7CIC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7CIC 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]] 1.78&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FZ0:2-azanyl-N-[3-(trifluoromethyloxy)phenyl]ethanamide'>FZ0</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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=7cic FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7cic OCA], [https://pdbe.org/7cic PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7cic RCSB], [https://www.ebi.ac.uk/pdbsum/7cic PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7cic ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/LPXC_PSEAE LPXC_PSEAE] Involved in the biosynthesis of lipid A, a phosphorylated glycolipid that anchors the lipopolysaccharide to the outer membrane of the cell.
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
UDP-3-O-acyl-N-acetylglucosamine deacetylase (LpxC) is a zinc metalloenzyme that catalyzes the first committed step in the biosynthesis of Lipid A, an essential component of the cell envelope of Gram-negative bacteria. The most advanced, disclosed LpxC inhibitors showing antibacterial activity coordinate zinc through a hydroxamate moiety with concerns about binding to other metalloenzymes. Here, we describe the discovery, optimization, and efficacy of two series of compounds derived from fragments with differing modes of zinc chelation. A series was evolved from a fragment where a glycine moiety complexes zinc, which achieved low nanomolar potency in an enzyme functional assay but poor antibacterial activity on cell cultures. A second series was based on a fragment that chelated zinc through an imidazole moiety. Structure-guided design led to a 2-(1S-hydroxyethyl)-imidazole derivative exhibiting low nanomolar inhibition of LpxC and a minimum inhibitory concentration (MIC) of 4 mug/mL against Pseudomonas aeruginosa, which is little affected by the presence of albumin.

Fragment-Based Discovery of Novel Non-Hydroxamate LpxC Inhibitors with Antibacterial Activity.,Yamada Y, Takashima H, Walmsley DL, Ushiyama F, Matsuda Y, Kanazawa H, Yamaguchi-Sasaki T, Tanaka-Yamamoto N, Yamagishi J, Kurimoto-Tsuruta R, Ogata Y, Ohtake N, Angove H, Baker L, Harris R, Macias A, Robertson A, Surgenor A, Watanabe H, Nakano K, Mima M, Iwamoto K, Okada A, Takata I, Hitaka K, Tanaka A, Fujita K, Sugiyama H, Hubbard RE J Med Chem. 2020 Nov 19. doi: 10.1021/acs.jmedchem.0c01215. PMID:33210531<ref>PMID:33210531</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7cic" style="background-color:#fffaf0;"></div>

==See Also==
*[[UDP-3-O-acyl-N-acetylglucosamine deacetylase|UDP-3-O-acyl-N-acetylglucosamine deacetylase]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Pseudomonas aeruginosa PAO1]]
[[Category: Baker LM]]
[[Category: Mima M]]
[[Category: Robertson A]]
[[Category: Surgenor A]]