8e4a: Difference between revisions

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<table><tr><td colspan='2'>[[8e4a]] is a 1 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=8E4A OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8E4A FirstGlance]. <br>
<table><tr><td colspan='2'>[[8e4a]] is a 1 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=8E4A OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8E4A 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]] 2.034&#8491;</td></tr>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.034&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=UFX:4-(4-cyclopropylbuta-1,3-diyn-1-yl)-N-[(2S,3S)-4,4-difluoro-3-hydroxy-1-(hydroxyamino)-3-methyl-1-oxobutan-2-yl]benzamide'>UFX</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=UFX:~{N}-[(2~{S},3~{S})-4,4-bis(fluoranyl)-3-methyl-3-oxidanyl-1-(oxidanylamino)-1-oxidanylidene-butan-2-yl]-4-(4-cyclopropylbuta-1,3-diynyl)benzamide'>UFX</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=8e4a FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8e4a OCA], [https://pdbe.org/8e4a PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8e4a RCSB], [https://www.ebi.ac.uk/pdbsum/8e4a PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8e4a ProSAT]</span></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=8e4a FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8e4a OCA], [https://pdbe.org/8e4a PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8e4a RCSB], [https://www.ebi.ac.uk/pdbsum/8e4a PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8e4a ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
[https://www.uniprot.org/uniprot/A0A072ZC86_PSEAI A0A072ZC86_PSEAI] 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.[HAMAP-Rule:MF_00388][SAAS:SAAS00531485]
[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 ==
The UDP-3-O-(R-3-hydroxyacyl)-N-acetylglucosamine deacetylase LpxC is an essential enzyme in the biosynthesis of lipid A, the outer membrane anchor of lipopolysaccharide and lipooligosaccharide in Gram-negative bacteria. The development of LpxC-targeting antibiotics toward clinical therapeutics has been hindered by the limited antibiotic profile of reported non-hydroxamate inhibitors and unexpected cardiovascular toxicity observed in certain hydroxamate and non-hydroxamate-based inhibitors. Here, we report the preclinical characterization of a slow, tight-binding LpxC inhibitor, LPC-233, with low picomolar affinity. The compound is a rapid bactericidal antibiotic, unaffected by established resistance mechanisms to commercial antibiotics, and displays outstanding activity against a wide range of Gram-negative clinical isolates in vitro. It is orally bioavailable and efficiently eliminates infections caused by susceptible and multidrug-resistant Gram-negative bacterial pathogens in murine soft tissue, sepsis, and urinary tract infection models. It displays exceptional in vitro and in vivo safety profiles, with no detectable adverse cardiovascular toxicity in dogs at 100 milligrams per kilogram. These results establish the feasibility of developing oral LpxC-targeting antibiotics for clinical applications.


Preclinical safety and efficacy characterization of an LpxC inhibitor against Gram-negative pathogens.,Zhao J, Cochrane CS, Najeeb J, Gooden D, Sciandra C, Fan P, Lemaitre N, Newns K, Nicholas RA, Guan Z, Thaden JT, Fowler VG Jr, Spasojevic I, Sebbane F, Toone EJ, Duncan C, Gammans R, Zhou P Sci Transl Med. 2023 Aug 9;15(708):eadf5668. doi: 10.1126/scitranslmed.adf5668. , Epub 2023 Aug 9. PMID:37556556<ref>PMID:37556556</ref>
==See Also==
 
*[[UDP-3-O-acyl-N-acetylglucosamine deacetylase 3D structures|UDP-3-O-acyl-N-acetylglucosamine deacetylase 3D structures]]
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8e4a" style="background-color:#fffaf0;"></div>
== References ==
<references/>
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