7ci4: Difference between revisions
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==Crystal structure of P.aeruginosa LpxC in complex with inhibitor== | ==Crystal structure of P.aeruginosa LpxC in complex with inhibitor== | ||
<StructureSection load='7ci4' size='340' side='right'caption='[[7ci4]]' scene=''> | <StructureSection load='7ci4' size='340' side='right'caption='[[7ci4]], [[Resolution|resolution]] 2.00Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7CI4 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=7CI4 FirstGlance]. <br> | <table><tr><td colspan='2'>[[7ci4]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Pseae Pseae]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7CI4 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=7CI4 FirstGlance]. <br> | ||
</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=7ci4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7ci4 OCA], [http://pdbe.org/7ci4 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=7ci4 RCSB], [http://www.ebi.ac.uk/pdbsum/7ci4 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=7ci4 ProSAT]</span></td></tr> | </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=FXU:(2R)-2-azanyl-4-methylsulfonyl-N-[3-(trifluoromethyloxy)phenyl]butanamide'>FXU</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | ||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">lpxC, envA, PA4406 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=208964 PSEAE])</td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/UDP-3-O-acyl-N-acetylglucosamine_deacetylase UDP-3-O-acyl-N-acetylglucosamine deacetylase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.5.1.108 3.5.1.108] </span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=7ci4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7ci4 OCA], [http://pdbe.org/7ci4 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=7ci4 RCSB], [http://www.ebi.ac.uk/pdbsum/7ci4 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=7ci4 ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Function == | |||
[[http://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®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 7ci4" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Baker | [[Category: Pseae]] | ||
[[Category: Mima M]] | [[Category: UDP-3-O-acyl-N-acetylglucosamine deacetylase]] | ||
[[Category: Robertson A]] | [[Category: Baker, L M]] | ||
[[Category: Surgenor A]] | [[Category: Mima, M]] | ||
[[Category: Robertson, A]] | |||
[[Category: Surgenor, A]] | |||
[[Category: Enva]] | |||
[[Category: Hydrolase]] | |||
[[Category: Lpxc]] | |||
[[Category: Pseudomonas aeruginosa]] | |||
[[Category: Udp-3-o-acyl-n-acetylglucosamine deacetylase]] | |||
Revision as of 14:06, 24 December 2020
Crystal structure of P.aeruginosa LpxC in complex with inhibitorCrystal structure of P.aeruginosa LpxC in complex with inhibitor
Structural highlights
Function[LPXC_PSEAE] Involved in the biosynthesis of lipid A, a phosphorylated glycolipid that anchors the lipopolysaccharide to the outer membrane of the cell. Publication Abstract from PubMedUDP-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[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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