View source for 6i48


==Structure of P. aeruginosa LpxC with compound 12: (2R)-4-(6-(2-Fluoro-4-methoxyphenyl)-3-oxo-1H-pyrrolo[1,2-c]imidazol-2(3H)-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide==
<StructureSection load='6i48' size='340' side='right'caption='[[6i48]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6i48]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Pseudomonas_aeruginosa_LESB58 Pseudomonas aeruginosa LESB58]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6I48 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6I48 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]] 2.196&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=H2H:(2~{R})-4-[6-(2-fluoranyl-4-methoxy-phenyl)-3-oxidanylidene-1~{H}-pyrrolo[1,2-c]imidazol-2-yl]-2-methyl-2-methylsulfonyl-~{N}-oxidanyl-butanamide'>H2H</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=6i48 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6i48 OCA], [https://pdbe.org/6i48 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6i48 RCSB], [https://www.ebi.ac.uk/pdbsum/6i48 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6i48 ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/LPXC_PSEA8 LPXC_PSEA8] Catalyzes the hydrolysis of UDP-3-O-myristoyl-N-acetylglucosamine to form UDP-3-O-myristoylglucosamine and acetate, the committed step in lipid A biosynthesis.
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
UDP-3-O-((R)-3-hydroxymyristoyl)-N-glucosamine deacetylase (LpxC) is as an attractive target for the discovery and development of novel antibacterial drugs to address the critical medical need created by multi-drug resistant Gram-negative bacteria. Using a scaffold hopping approach on a known family of methylsulfone hydroxamate LpxC inhibitors, several hit series eliciting potent antibacterial activities against Enterobacteriaceae and Pseudomonas aeruginosa were identified. Subsequent hit-to-lead optimization, using co-crystal structures of inhibitors bound to Pseudomonas aeruginosa LpxC as guides, resulted in the discovery of multiple chemical series based on i) isoindolin-1-ones, ii) 4,5-dihydro-6H-thieno[2,3-c]pyrrol-6-ones and iii) 1,2-dihydro-3H-pyrrolo[1,2-c]imidazole-3-ones. Synthetic methods, antibacterial activities and relative binding affinities, as well as physico-chemical properties that allowed compound prioritization are presented. Finally, in vivo properties of lead molecules which belong to the most promising pyrrolo-imidazolone series such as 18d, are discussed.

Discovery of Novel Inhibitors of LpxC Displaying Potent In Vitro Activity against Gram-Negative Bacteria.,Surivet JP, Panchaud P, Specklin JL, Diethelm S, Blumstein AC, Gauvin JC, Jacob L, Masse F, Mathieu G, Mirre A, Schmitt C, Lange R, Tidten-Luksch N, Gnerre C, Seeland S, Herrmann C, Seiler P, Enderlin-Paput M, Mac Sweeney A, Wicki M, Hubschwerlen C, Ritz D, Rueedi G J Med Chem. 2019 Dec 5. doi: 10.1021/acs.jmedchem.9b01604. PMID:31804826<ref>PMID:31804826</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6i48" 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 LESB58]]
[[Category: Blumstein A-C]]
[[Category: Bur D]]
[[Category: Diethelm S]]
[[Category: Enderlin-Paput M]]
[[Category: Gauvin J-C]]
[[Category: Gnerre C]]
[[Category: Hermann C]]
[[Category: Hubschwerlen C]]
[[Category: Jacob L]]
[[Category: Lange R]]
[[Category: Locher HH]]
[[Category: Mac Sweeney A]]
[[Category: Masse F]]
[[Category: Mathieu G]]
[[Category: Mirre A]]
[[Category: Panchaud P]]
[[Category: Ritz D]]
[[Category: Rueedi G]]
[[Category: Schmitt C]]
[[Category: Seeland S]]
[[Category: Seiler P]]
[[Category: Specklin J-L]]
[[Category: Surivet J-P]]
[[Category: Tidten-Luksch N]]