OCA at 15:19, 18 October 2023

2023-10-18T15:19:57Z

←Older revision		Revision as of 15:19, 18 October 2023
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	==Crystal Structure of P. aeruginosa LpxC with N-Hydroxyformamide inhibitor==		==Crystal Structure of P. aeruginosa LpxC with N-Hydroxyformamide inhibitor==
-	<StructureSection load='7k9a' size='340' side='right'caption='[[7k9a]]' scene=''>	+	<StructureSection load='7k9a' size='340' side='right'caption='[[7k9a]], [[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=7K9A OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://proteopedia.org/fgij/fg.htm?mol=7K9A FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[7k9a]] 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=7K9A OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7K9A 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=7k9a FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7k9a OCA], [~~http~~://pdbe.org/7k9a PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=7k9a RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/7k9a PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=7k9a ProSAT]</span></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]] 2Å</td></tr>
		+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=W4P:N-hydroxy-N-[(1S)-2-{5-[(4-{[2-(hydroxymethyl)-1H-imidazol-1-yl]methyl}phenyl)ethynyl]-1H-benzotriazol-1-yl}-1-(methylsulfanyl)ethyl]formamide'>W4P</scene>, <scene name='pdbligand=W8P:N-hydroxy-N-[(1R)-2-{5-[(4-{[2-(hydroxymethyl)-1H-imidazol-1-yl]methyl}phenyl)ethynyl]-1H-benzotriazol-1-yl}-1-(methylsulfanyl)ethyl]formamide'>W8P</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=7k9a FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7k9a OCA], [https://pdbe.org/7k9a PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7k9a RCSB], [https://www.ebi.ac.uk/pdbsum/7k9a PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7k9a ProSAT]</span></td></tr>
	</table>		</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-(R-3-hydroxyacyl)-N-acetylglucosamine deacetylase (LpxC), the zinc metalloenzyme catalyzing the first committed step of lipid A biosynthesis in Gram-negative bacteria, has been a target for antibacterial drug discovery for many years. All inhibitor chemotypes reaching an advanced preclinical stage and clinical phase 1 have contained terminal hydroxamic acid, and none have been successfully advanced due, in part, to safety concerns, including hemodynamic effects. We hypothesized that the safety of LpxC inhibitors could be improved by replacing the terminal hydroxamic acid with a different zinc-binding group. After choosing an N-hydroxyformamide zinc-binding group, we investigated the structure-activity relationship of each part of the inhibitor scaffold with respect to Pseudomonas aeruginosa and Escherichia coli LpxC binding affinity, in vitro antibacterial potency and pharmacological properties. We identified a novel, potency-enhancing hydrophobic binding interaction for an LpxC inhibitor. We demonstrated in vivo efficacy of one compound in a neutropenic mouse E. coli infection model. Another compound was tested in a rat hemodynamic assay and was found to have a hypotensive effect. This result demonstrated that replacing the terminal hydroxamic acid with a different zinc-binding group was insufficient to avoid this previously recognized safety issue with LpxC inhibitors.
		+
		+	N-Hydroxyformamide LpxC inhibitors, their in vivo efficacy in a mouse Escherichia coli infection model, and their safety in a rat hemodynamic assay.,Furuya T, Shapiro AB, Comita-Prevoir J, Kuenstner EJ, Zhang J, Ribe SD, Chen A, Hines D, Moussa SH, Carter NM, Sylvester MA, Romero JAC, Vega CV, Sacco MD, Chen Y, O'Donnell JP, Durand-Reville TF, Miller AA, Tommasi RA Bioorg Med Chem. 2020 Oct 28;28(24):115826. doi: 10.1016/j.bmc.2020.115826. PMID:33160146<ref>PMID:33160146</ref>
		+
		+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>
		+	<div class="pdbe-citations 7k9a" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[UDP-3-O-acyl-N-acetylglucosamine deacetylase\|UDP-3-O-acyl-N-acetylglucosamine deacetylase]]
		+	== References ==
		+	<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
	[[Category: Large Structures]]		[[Category: Large Structures]]
		+	[[Category: Pseudomonas aeruginosa PAO1]]
	[[Category: Chen Y]]		[[Category: Chen Y]]
	[[Category: Sacco M]]		[[Category: Sacco M]]

OCA at 07:00, 25 November 2020

2020-11-25T07:00:14Z

←Older revision		Revision as of 07:00, 25 November 2020
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-	'''Unreleased structure'''

-	~~The entry 7k9a is ON HOLD until Paper Publication~~	+	==Crystal Structure of P. aeruginosa LpxC with N-Hydroxyformamide inhibitor==
-		+	<StructureSection load='7k9a' size='340' side='right'caption='[[7k9a]]' scene=''>
-	~~Authors: Sacco, M., Chen, Y.~~	+	== Structural highlights ==
-		+	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7K9A OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=7K9A FirstGlance]. <br>
-	~~Description:~~ Crystal Structure of P. aeruginosa LpxC with N-Hydroxyformamide inhibitor	+	</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=7k9a FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7k9a OCA], [http://pdbe.org/7k9a PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=7k9a RCSB], [http://www.ebi.ac.uk/pdbsum/7k9a PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=7k9a ProSAT]</span></td></tr>
-	[[Category: ~~Unreleased~~ Structures]]	+	</table>
-	[[Category: Chen, Y]]	+	__TOC__
-	[[Category: Sacco, M]]	+	</StructureSection>
		+	[[Category: Large Structures]]
		+	[[Category: Chen Y]]
		+	[[Category: Sacco M]]

OCA: Protected "7k9a" [edit=sysop:move=sysop]

2020-10-07T04:47:34Z

Protected "7k9a" [edit=sysop:move=sysop]

←Older revision

Revision as of 04:47, 7 October 2020

OCA: New page: '''Unreleased structure''' The entry 7k9a is ON HOLD until Paper Publication Authors: Sacco, M., Chen, Y. Description: Crystal Structure of P. aeruginosa LpxC with N-Hydroxyformamide i...

2020-10-07T04:47:32Z

New page: '''Unreleased structure''' The entry 7k9a is ON HOLD until Paper Publication Authors: Sacco, M., Chen, Y. Description: Crystal Structure of P. aeruginosa LpxC with N-Hydroxyformamide i...

New page

'''Unreleased structure'''

The entry 7k9a is ON HOLD until Paper Publication

Authors: Sacco, M., Chen, Y.

Description: Crystal Structure of P. aeruginosa LpxC with N-Hydroxyformamide inhibitor
[[Category: Unreleased Structures]]
[[Category: Chen, Y]]
[[Category: Sacco, M]]

7k9a - Revision history

OCA at 15:19, 18 October 2023

OCA at 07:00, 25 November 2020

OCA: Protected "7k9a" [edit=sysop:move=sysop]

OCA: New page: '''Unreleased structure''' The entry 7k9a is ON HOLD until Paper Publication Authors: Sacco, M., Chen, Y. Description: Crystal Structure of P. aeruginosa LpxC with N-Hydroxyformamide i...