7t60 - Revision history

OCA at 17:00, 18 October 2023

2023-10-18T17:00:49Z

←Older revision		Revision as of 17:00, 18 October 2023
Line 4:		Line 4:
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[7t60]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Pseudomonas_aeruginosa_PA7 Pseudomonas aeruginosa PA7]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7T60 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7T60 FirstGlance]. <br>		<table><tr><td colspan='2'>[[7t60]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Pseudomonas_aeruginosa_PA7 Pseudomonas aeruginosa PA7]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7T60 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7T60 FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=F9H:(3S)-3-(5,5-dimethyl-2-oxo-1,3-oxazolidin-3-yl)-N-(1H-tetrazol-5-yl)-1-[3-(trifluoromethyl)benzoyl]-2,3-dihydro-1H-indole-3-carboxamide'>F9H</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=TRS:2-AMINO-2-HYDROXYMETHYL-PROPANE-1,3-DIOL'>TRS</scene></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=F9H:(3S)-3-(5,5-dimethyl-2-oxo-1,3-oxazolidin-3-yl)-N-(1H-tetrazol-5-yl)-1-[3-(trifluoromethyl)benzoyl]-2,3-dihydro-1H-indole-3-carboxamide'>F9H</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=TRS:2-AMINO-2-HYDROXYMETHYL-PROPANE-1,3-DIOL'>TRS</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=7t60 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7t60 OCA], [https://pdbe.org/7t60 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7t60 RCSB], [https://www.ebi.ac.uk/pdbsum/7t60 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7t60 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=7t60 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7t60 OCA], [https://pdbe.org/7t60 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7t60 RCSB], [https://www.ebi.ac.uk/pdbsum/7t60 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7t60 ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
-	[[https://www.uniprot.org/uniprot/LPXA_PSEA7 LPXA_PSEA7]] Involved in the biosynthesis of lipid A, a phosphorylated glycolipid that anchors the lipopolysaccharide to the outer membrane of the cell.	+	[https://www.uniprot.org/uniprot/LPXA_PSEA7 LPXA_PSEA7] Involved in the biosynthesis of lipid A, a phosphorylated glycolipid that anchors the lipopolysaccharide to the outer membrane of the cell.
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>

OCA at 05:28, 8 September 2022

2022-09-08T05:28:32Z

←Older revision		Revision as of 05:28, 8 September 2022
Line 3:		Line 3:
	<StructureSection load='7t60' size='340' side='right'caption='[[7t60]], [[Resolution\|resolution]] 2.00Å' scene=''>		<StructureSection load='7t60' size='340' side='right'caption='[[7t60]], [[Resolution\|resolution]] 2.00Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[7t60]] is a 6 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7T60 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7T60 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[7t60]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Pseudomonas_aeruginosa_PA7 Pseudomonas aeruginosa PA7]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7T60 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7T60 FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=F9H:(3S)-3-(5,5-dimethyl-2-oxo-1,3-oxazolidin-3-yl)-N-(1H-tetrazol-5-yl)-1-[3-(trifluoromethyl)benzoyl]-2,3-dihydro-1H-indole-3-carboxamide'>F9H</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=TRS:2-AMINO-2-HYDROXYMETHYL-PROPANE-1,3-DIOL'>TRS</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=F9H:(3S)-3-(5,5-dimethyl-2-oxo-1,3-oxazolidin-3-yl)-N-(1H-tetrazol-5-yl)-1-[3-(trifluoromethyl)benzoyl]-2,3-dihydro-1H-indole-3-carboxamide'>F9H</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=TRS:2-AMINO-2-HYDROXYMETHYL-PROPANE-1,3-DIOL'>TRS</scene></td></tr>
-	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Acyl-[acyl-carrier-protein]--UDP-N-acetylglucosamine_O-acyltransferase Acyl-[acyl-carrier-protein]--UDP-N-acetylglucosamine O-acyltransferase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.3.1.129 2.3.1.129] </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=7t60 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7t60 OCA], [https://pdbe.org/7t60 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7t60 RCSB], [https://www.ebi.ac.uk/pdbsum/7t60 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7t60 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=7t60 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7t60 OCA], [https://pdbe.org/7t60 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7t60 RCSB], [https://www.ebi.ac.uk/pdbsum/7t60 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7t60 ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
-	[[https://www.uniprot.org/uniprot/LPXA_PSEA7 LPXA_PSEA7]] Involved in the biosynthesis of lipid A, a phosphorylated glycolipid that anchors the lipopolysaccharide to the outer membrane of the cell.	+	[[https://www.uniprot.org/uniprot/LPXA_PSEA7 LPXA_PSEA7]] 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 ==~~	+
-	Enzymes involved in lipid A biosynthesis are promising antibacterial drug targets in Gram-negative bacteria. In this study, we use a structure-based design approach to develop a series of novel tetrazole ligands with low muM affinity for LpxA, the first enzyme in the lipid A pathway. Aided by previous structural data, X-ray crystallography, and surface plasmon resonance bioanalysis, we identify 17 hit compounds. Two of these hits were subsequently modified to optimize interactions with three regions of the LpxA active site. This strategy ultimately led to the discovery of ligand L13, which had a KD of 3.0 muM. The results reveal new chemical scaffolds as potential LpxA inhibitors, important binding features for ligand optimization, and protein conformational changes in response to ligand binding. Specifically, they show that a tetrazole ring is well-accommodated in a small cleft formed between Met169, the "hydrophobic-ruler" and His156, both of which demonstrate significant conformational flexibility. Furthermore, we find that the acyl-chain binding pocket is the most tractable region of the active site for realizing affinity gains and, along with a neighboring patch of hydrophobic residues, preferentially binds aliphatic and aromatic groups. The results presented herein provide valuable chemical and structural information for future inhibitor discovery against this important antibacterial drug target.	+
-		+
-	Structure-Based Ligand Design Targeting Pseudomonas aeruginosa LpxA in Lipid A Biosynthesis.,Sacco MD, Defrees K, Zhang X, Lawless W, Nwanochie E, Balsizer A, Darch SE, Renslo AR, Chen Y ACS Infect Dis. 2022 Jul 8;8(7):1231-1240. doi: 10.1021/acsinfecdis.1c00650. Epub, 2022 Jun 2. PMID:35653508<ref>PMID:35653508</ref>	+
-		+
-	~~From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>~~	+
-	~~</div>~~	+
-	~~<div class="pdbe-citations 7t60" style="background-color:#fffaf0;"></div>~~	+
-	~~== References ==~~	+
-	~~<references/>~~	+
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: ~~Chen, Y~~]]	+	[[Category: Pseudomonas aeruginosa PA7]]
-	[[Category: ~~Sacco, M~~]]	+	[[Category: Chen Y]]
-	[[Category: ~~Lipid some]]~~	+	[[Category: Sacco M]]
-	~~[[Category: Lipopolysaccharide]]~~	+
-	~~[[Category: Lp]]~~	+
-	~~[[Category: Lpxa]]~~	+
-	~~[[Category: Transferase]]~~	+
-	~~[[Category: Udp-n-acetylglucosamine o-acyltransferase~~]]	+

OCA at 05:26, 13 July 2022

2022-07-13T05:26:28Z

←Older revision		Revision as of 05:26, 13 July 2022
Line 1:		Line 1:

	==P. aeruginosa LpxA in complex with ligand L13==		==P. aeruginosa LpxA in complex with ligand L13==
-	<StructureSection load='7t60' size='340' side='right'caption='[[7t60]]' scene=''>	+	<StructureSection load='7t60' size='340' side='right'caption='[[7t60]], [[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=7T60 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7T60 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[7t60]] is a 6 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7T60 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7T60 FirstGlance]. <br>
-	</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=7t60 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7t60 OCA], [https://pdbe.org/7t60 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7t60 RCSB], [https://www.ebi.ac.uk/pdbsum/7t60 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7t60 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=F9H:(3S)-3-(5,5-dimethyl-2-oxo-1,3-oxazolidin-3-yl)-N-(1H-tetrazol-5-yl)-1-[3-(trifluoromethyl)benzoyl]-2,3-dihydro-1H-indole-3-carboxamide'>F9H</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=TRS:2-AMINO-2-HYDROXYMETHYL-PROPANE-1,3-DIOL'>TRS</scene></td></tr>
		+	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Acyl-[acyl-carrier-protein]--UDP-N-acetylglucosamine_O-acyltransferase Acyl-[acyl-carrier-protein]--UDP-N-acetylglucosamine O-acyltransferase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.3.1.129 2.3.1.129] </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=7t60 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7t60 OCA], [https://pdbe.org/7t60 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7t60 RCSB], [https://www.ebi.ac.uk/pdbsum/7t60 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7t60 ProSAT]</span></td></tr>
	</table>		</table>
		+	== Function ==
		+	[[https://www.uniprot.org/uniprot/LPXA_PSEA7 LPXA_PSEA7]] 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 ==
		+	Enzymes involved in lipid A biosynthesis are promising antibacterial drug targets in Gram-negative bacteria. In this study, we use a structure-based design approach to develop a series of novel tetrazole ligands with low muM affinity for LpxA, the first enzyme in the lipid A pathway. Aided by previous structural data, X-ray crystallography, and surface plasmon resonance bioanalysis, we identify 17 hit compounds. Two of these hits were subsequently modified to optimize interactions with three regions of the LpxA active site. This strategy ultimately led to the discovery of ligand L13, which had a KD of 3.0 muM. The results reveal new chemical scaffolds as potential LpxA inhibitors, important binding features for ligand optimization, and protein conformational changes in response to ligand binding. Specifically, they show that a tetrazole ring is well-accommodated in a small cleft formed between Met169, the "hydrophobic-ruler" and His156, both of which demonstrate significant conformational flexibility. Furthermore, we find that the acyl-chain binding pocket is the most tractable region of the active site for realizing affinity gains and, along with a neighboring patch of hydrophobic residues, preferentially binds aliphatic and aromatic groups. The results presented herein provide valuable chemical and structural information for future inhibitor discovery against this important antibacterial drug target.
		+
		+	Structure-Based Ligand Design Targeting Pseudomonas aeruginosa LpxA in Lipid A Biosynthesis.,Sacco MD, Defrees K, Zhang X, Lawless W, Nwanochie E, Balsizer A, Darch SE, Renslo AR, Chen Y ACS Infect Dis. 2022 Jul 8;8(7):1231-1240. doi: 10.1021/acsinfecdis.1c00650. Epub, 2022 Jun 2. PMID:35653508<ref>PMID:35653508</ref>
		+
		+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>
		+	<div class="pdbe-citations 7t60" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: Chen Y]]	+	[[Category: Chen, Y]]
-	[[Category: Sacco M]]	+	[[Category: Sacco, M]]
		+	[[Category: Lipid some]]
		+	[[Category: Lipopolysaccharide]]
		+	[[Category: Lp]]
		+	[[Category: Lpxa]]
		+	[[Category: Transferase]]
		+	[[Category: Udp-n-acetylglucosamine o-acyltransferase]]

OCA at 16:14, 6 July 2022

2022-07-06T16:14:08Z

←Older revision		Revision as of 16:14, 6 July 2022
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 7t60 ~~is ON HOLD until Paper Publication~~	+	==P. aeruginosa LpxA in complex with ligand L13==
-		+	<StructureSection load='7t60' size='340' side='right'caption='[[7t60]]' 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=7T60 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7T60 FirstGlance]. <br>
-	~~Description~~: P. ~~aeruginosa LpxA in complex with ligand L13~~	+	</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=7t60 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7t60 OCA], [https://pdbe.org/7t60 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7t60 RCSB], [https://www.ebi.ac.uk/pdbsum/7t60 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7t60 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 at 05:55, 19 January 2022

2022-01-19T05:55:43Z

←Older revision		Revision as of 05:55, 19 January 2022
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 7t60 is ON HOLD	+	The entry 7t60 is ON HOLD until Paper Publication

	Authors: Sacco, M., Chen, Y.		Authors: Sacco, M., Chen, Y.

OCA: Protected "7t60" [edit=sysop:move=sysop]

2021-12-22T14:06:13Z

Protected "7t60" [edit=sysop:move=sysop]

←Older revision

Revision as of 14:06, 22 December 2021

OCA: New page: '''Unreleased structure''' The entry 7t60 is ON HOLD Authors: Sacco, M., Chen, Y. Description: P. aeruginosa LpxA in complex with ligand L13 Category: Unreleased Structures [[Categ...

2021-12-22T14:06:12Z

New page: '''Unreleased structure''' The entry 7t60 is ON HOLD Authors: Sacco, M., Chen, Y. Description: P. aeruginosa LpxA in complex with ligand L13 Category: Unreleased Structures [[Categ...

New page

'''Unreleased structure'''

The entry 7t60 is ON HOLD

Authors: Sacco, M., Chen, Y.

Description: P. aeruginosa LpxA in complex with ligand L13
[[Category: Unreleased Structures]]
[[Category: Chen, Y]]
[[Category: Sacco, M]]