5u3b: Difference between revisions

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'''Unreleased structure'''


The entry 5u3b is ON HOLD  until Paper Publication
==Pseudomonas aeruginosa LpxC in complex with NVS-LPXC-01==
<StructureSection load='5u3b' size='340' side='right' caption='[[5u3b]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5u3b]] 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=5U3B OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5U3B FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=7TD:N-[(2S)-3-amino-1-(hydroxyamino)-3-methyl-1-oxobutan-2-yl]-4-[(but-2-yn-1-yl)oxy]benzamide'>7TD</scene>, <scene name='pdbligand=EPE:4-(2-HYDROXYETHYL)-1-PIPERAZINE+ETHANESULFONIC+ACID'>EPE</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5u39|5u39]]</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://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5u3b FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5u3b OCA], [http://pdbe.org/5u3b PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5u3b RCSB], [http://www.ebi.ac.uk/pdbsum/5u3b PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5u3b ProSAT]</span></td></tr>
</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 ==
Over the past several decades, the frequency of antibacterial resistance in hospitals, including multidrug resistance (MDR) and its association with serious infectious diseases, has increased at alarming rates. Pseudomonas aeruginosa is a leading cause of nosocomial infections, and resistance to virtually all approved antibacterial agents is emerging in this pathogen. To address the need for new agents to treat MDR P. aeruginosa, we focused on inhibiting the first committed step in the biosynthesis of lipid A, the deacetylation of uridyldiphospho-3-O-(R-hydroxydecanoyl)-N-acetylglucosamine by the enzyme LpxC. We approached this through the design, synthesis, and biological evaluation of novel hydroxamic acid LpxC inhibitors, exemplified by 1, where cytotoxicity against mammalian cell lines was reduced, solubility and plasma-protein binding were improved while retaining potent anti-pseudomonal activity in vitro and in vivo.


Authors:  
Design, Synthesis, and Properties of a Potent Inhibitor of Pseudomonas aeruginosa Deacetylase LpxC.,Piizzi G, Parker DT, Peng Y, Dobler M, Patnaik A, Wattanasin S, Liu E, Lenoir F, Nunez J, Kerrigan J, McKenney D, Osborne C, Yu D, Lanieri L, Bojkovic J, Dzink-Fox J, Lilly MD, Sprague ER, Lu Y, Wang H, Ranjitkar S, Xie L, Wang B, Glick M, Hamann LG, Tommasi R, Yang X, Dean CR J Med Chem. 2017 Jun 22;60(12):5002-5014. doi: 10.1021/acs.jmedchem.7b00377. Epub, 2017 Jun 9. PMID:28549219<ref>PMID:28549219</ref>


Description:  
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
[[Category: Unreleased Structures]]
</div>
<div class="pdbe-citations 5u3b" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Pseae]]
[[Category: UDP-3-O-acyl-N-acetylglucosamine deacetylase]]
[[Category: Sprague, E R]]
[[Category: Gram negative]]
[[Category: Hydrolase]]
[[Category: Hydroxymate]]
[[Category: Lpxc]]

Revision as of 11:15, 16 November 2017

Pseudomonas aeruginosa LpxC in complex with NVS-LPXC-01Pseudomonas aeruginosa LpxC in complex with NVS-LPXC-01

Structural highlights

5u3b is a 2 chain structure with sequence from Pseae. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:, ,
Gene:lpxC, envA, PA4406 (PSEAE)
Activity:UDP-3-O-acyl-N-acetylglucosamine deacetylase, with EC number 3.5.1.108
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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 PubMed

Over the past several decades, the frequency of antibacterial resistance in hospitals, including multidrug resistance (MDR) and its association with serious infectious diseases, has increased at alarming rates. Pseudomonas aeruginosa is a leading cause of nosocomial infections, and resistance to virtually all approved antibacterial agents is emerging in this pathogen. To address the need for new agents to treat MDR P. aeruginosa, we focused on inhibiting the first committed step in the biosynthesis of lipid A, the deacetylation of uridyldiphospho-3-O-(R-hydroxydecanoyl)-N-acetylglucosamine by the enzyme LpxC. We approached this through the design, synthesis, and biological evaluation of novel hydroxamic acid LpxC inhibitors, exemplified by 1, where cytotoxicity against mammalian cell lines was reduced, solubility and plasma-protein binding were improved while retaining potent anti-pseudomonal activity in vitro and in vivo.

Design, Synthesis, and Properties of a Potent Inhibitor of Pseudomonas aeruginosa Deacetylase LpxC.,Piizzi G, Parker DT, Peng Y, Dobler M, Patnaik A, Wattanasin S, Liu E, Lenoir F, Nunez J, Kerrigan J, McKenney D, Osborne C, Yu D, Lanieri L, Bojkovic J, Dzink-Fox J, Lilly MD, Sprague ER, Lu Y, Wang H, Ranjitkar S, Xie L, Wang B, Glick M, Hamann LG, Tommasi R, Yang X, Dean CR J Med Chem. 2017 Jun 22;60(12):5002-5014. doi: 10.1021/acs.jmedchem.7b00377. Epub, 2017 Jun 9. PMID:28549219[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

  1. ↑ Piizzi G, Parker DT, Peng Y, Dobler M, Patnaik A, Wattanasin S, Liu E, Lenoir F, Nunez J, Kerrigan J, McKenney D, Osborne C, Yu D, Lanieri L, Bojkovic J, Dzink-Fox J, Lilly MD, Sprague ER, Lu Y, Wang H, Ranjitkar S, Xie L, Wang B, Glick M, Hamann LG, Tommasi R, Yang X, Dean CR. Design, Synthesis, and Properties of a Potent Inhibitor of Pseudomonas aeruginosa Deacetylase LpxC. J Med Chem. 2017 Jun 22;60(12):5002-5014. doi: 10.1021/acs.jmedchem.7b00377. Epub, 2017 Jun 9. PMID:28549219 doi:http://dx.doi.org/10.1021/acs.jmedchem.7b00377

5u3b, resolution 2.00Å

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