6chl - Revision history

OCA at 14:28, 13 March 2024

OCA — Wed, 13 Mar 2024 14:28:23 GMT

←Older revision		Revision as of 14:28, 13 March 2024
Line 3:		Line 3:
	<StructureSection load='6chl' size='340' side='right'caption='[[6chl]], [[Resolution\|resolution]] 2.20Å' scene=''>		<StructureSection load='6chl' size='340' side='right'caption='[[6chl]], [[Resolution\|resolution]] 2.20Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[6chl]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6CHL OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://proteopedia.org/fgij/fg.htm?mol=6CHL FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[6chl]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Escherichia_coli_K-12 Escherichia coli K-12]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6CHL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6CHL FirstGlance]. <br>
-	</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=EXJ:(3R)-3-(3-chlorophenyl)-3-[(5-methyl-7-oxo-6,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)amino]propanenitrile'>EXJ</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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]] 2.2Å</td></tr>
-	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Pantetheine-phosphate_adenylyltransferase Pantetheine-phosphate adenylyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.7.3 2.7.7.3] </span></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=EXJ:(3R)-3-(3-chlorophenyl)-3-[(5-methyl-7-oxo-6,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)amino]propanenitrile'>EXJ</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></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=6chl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6chl OCA], [~~http~~://pdbe.org/6chl PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=6chl RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/6chl PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=6chl 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=6chl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6chl OCA], [https://pdbe.org/6chl PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6chl RCSB], [https://www.ebi.ac.uk/pdbsum/6chl PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6chl ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
-	[~~[http~~://www.uniprot.org/uniprot/COAD_ECOLI COAD_ECOLI]] Reversibly transfers an adenylyl group from ATP to 4'-phosphopantetheine, yielding dephospho-CoA (dPCoA) and pyrophosphate.	+	[https://www.uniprot.org/uniprot/COAD_ECOLI COAD_ECOLI] Reversibly transfers an adenylyl group from ATP to 4'-phosphopantetheine, yielding dephospho-CoA (dPCoA) and pyrophosphate.
-	~~<div style="background-color:#fffaf0;">~~	+
-	~~== Publication Abstract from PubMed ==~~	+
-	In the preceding manuscript we described a successful fragment-based lead discovery (FBLD) strategy for discovery of bacterial phosphopantetheine adenylyltransferase inhibitors (PPAT, CoaD). Following several rounds of optimization two promising lead compounds were identified: triazolopyrimidinone 3 and 4-azabenzimidazole 4. Here we disclose our efforts to further optimize these two leads for on-target potency and Gram-negative cellular activity. Enabled by a robust X-ray crystallography system, our structure-based inhibitor design approach delivered compounds with biochemical potencies 4-5 orders of magnitude greater than their respective fragment starting points. Additional optimization was guided by observations on bacterial permeability and physicochemical properties, which ultimately led to the identification of PPAT inhibitors with cellular activity against wild-type E. coli.	+
-		+
-	Discovery and Optimization of Phosphopantetheine Adenylyltransferase Inhibitors with Gram-Negative Antibacterial Activity.,Skepper CK, Moreau RJ, Appleton BA, Benton BM, Drumm JE, Feng BY, Geng M, Lingel A, Lu Y, Mamo M, Mergo W, Mostafavi M, Rath CM, Steffek M, Takeoka KT, Uehara K, Wang L, Wei JR, Xie L, Xu W, Zhang Q, Li C, de Vicente J J Med Chem. 2018 Mar 18. doi: 10.1021/acs.jmedchem.7b01861. PMID:29551072<ref>PMID:29551072</ref>	+
-		+
-	~~From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>~~	+
-	~~</div>~~	+
-	~~<div class="pdbe-citations 6chl" style="background-color:#fffaf0;"></div>~~	+
-	~~== References ==~~	+
-	~~<references/>~~	+
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Escherichia coli K-12]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	~~[[Category: Pantetheine-phosphate adenylyltransferase]]~~	+	[[Category: Appleton BA]]
-	[[Category: Appleton~~, B A~~]]	+	[[Category: Mamo M]]
-	[[Category: Mamo, M]]	+
-	~~[[Category: Fbdd gram-negative antibacterial antibiotic]]~~	+
-	~~[[Category: Ppat caad]]~~	+
-	~~[[Category: Transferase transferase-antibiotic complex]]~~	+
-	~~[[Category: Transferase-antibiotic complex~~]]	+

OCA at 08:57, 11 November 2020

OCA — Wed, 11 Nov 2020 08:57:22 GMT

←Older revision		Revision as of 08:57, 11 November 2020
Line 1:		Line 1:

	==Phosphopantetheine adenylyltransferase (CoaD) in complex with (R)-3-(3-chlorophenyl)-3-((5-methyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)amino)propanenitrile==		==Phosphopantetheine adenylyltransferase (CoaD) in complex with (R)-3-(3-chlorophenyl)-3-((5-methyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)amino)propanenitrile==
-	<StructureSection load='6chl' size='340' side='right' caption='[[6chl]], [[Resolution\|resolution]] 2.20Å' scene=''>	+	<StructureSection load='6chl' size='340' side='right'caption='[[6chl]], [[Resolution\|resolution]] 2.20Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[6chl]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6CHL OCA]. For a <b>guided tour on the structure components</b> use [http://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=6CHL FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[6chl]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6CHL OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6CHL FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=EXJ:(3R)-3-(3-chlorophenyl)-3-[(5-methyl-7-oxo-6,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)amino]propanenitrile'>EXJ</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>	+	</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=EXJ:(3R)-3-(3-chlorophenyl)-3-[(5-methyl-7-oxo-6,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)amino]propanenitrile'>EXJ</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Pantetheine-phosphate_adenylyltransferase Pantetheine-phosphate adenylyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.7.3 2.7.7.3] </span></td></tr>		<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Pantetheine-phosphate_adenylyltransferase Pantetheine-phosphate adenylyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.7.3 2.7.7.3] </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=6chl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6chl OCA], [http://pdbe.org/6chl PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6chl RCSB], [http://www.ebi.ac.uk/pdbsum/6chl PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6chl ProSAT]</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=6chl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6chl OCA], [http://pdbe.org/6chl PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6chl RCSB], [http://www.ebi.ac.uk/pdbsum/6chl PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6chl ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
Line 23:		Line 23:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Large Structures]]
	[[Category: Pantetheine-phosphate adenylyltransferase]]		[[Category: Pantetheine-phosphate adenylyltransferase]]
	[[Category: Appleton, B A]]		[[Category: Appleton, B A]]

OCA at 05:59, 4 April 2018

OCA — Wed, 04 Apr 2018 05:59:26 GMT

←Older revision		Revision as of 05:59, 4 April 2018
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 6chl is ~~ON HOLD until Paper~~ Publication	+	==Phosphopantetheine adenylyltransferase (CoaD) in complex with (R)-3-(3-chlorophenyl)-3-((5-methyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)amino)propanenitrile==
		+	<StructureSection load='6chl' size='340' side='right' caption='[[6chl]], [[Resolution\|resolution]] 2.20Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[6chl]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6CHL OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6CHL FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=EXJ:(3R)-3-(3-chlorophenyl)-3-[(5-methyl-7-oxo-6,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)amino]propanenitrile'>EXJ</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
		+	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Pantetheine-phosphate_adenylyltransferase Pantetheine-phosphate adenylyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.7.3 2.7.7.3] </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=6chl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6chl OCA], [http://pdbe.org/6chl PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6chl RCSB], [http://www.ebi.ac.uk/pdbsum/6chl PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6chl ProSAT]</span></td></tr>
		+	</table>
		+	== Function ==
		+	[[http://www.uniprot.org/uniprot/COAD_ECOLI COAD_ECOLI]] Reversibly transfers an adenylyl group from ATP to 4'-phosphopantetheine, yielding dephospho-CoA (dPCoA) and pyrophosphate.
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	In the preceding manuscript we described a successful fragment-based lead discovery (FBLD) strategy for discovery of bacterial phosphopantetheine adenylyltransferase inhibitors (PPAT, CoaD). Following several rounds of optimization two promising lead compounds were identified: triazolopyrimidinone 3 and 4-azabenzimidazole 4. Here we disclose our efforts to further optimize these two leads for on-target potency and Gram-negative cellular activity. Enabled by a robust X-ray crystallography system, our structure-based inhibitor design approach delivered compounds with biochemical potencies 4-5 orders of magnitude greater than their respective fragment starting points. Additional optimization was guided by observations on bacterial permeability and physicochemical properties, which ultimately led to the identification of PPAT inhibitors with cellular activity against wild-type E. coli.

-	~~Authors:~~ Mamo, M., ~~Appleton~~, B.A.	+	Discovery and Optimization of Phosphopantetheine Adenylyltransferase Inhibitors with Gram-Negative Antibacterial Activity.,Skepper CK, Moreau RJ, Appleton BA, Benton BM, Drumm JE, Feng BY, Geng M, Lingel A, Lu Y, Mamo M, Mergo W, Mostafavi M, Rath CM, Steffek M, Takeoka KT, Uehara K, Wang L, Wei JR, Xie L, Xu W, Zhang Q, Li C, de Vicente J J Med Chem. 2018 Mar 18. doi: 10.1021/acs.jmedchem.7b01861. PMID:29551072<ref>PMID:29551072</ref>

-	~~Description: Phosphopantetheine adenylyltransferase (CoaD) in complex with (R)-3-(3-chlorophenyl)-3-((5-methyl-7-oxo-4~~,~~7-dihydro-[1,2,4]triazolo[1,5-~~a~~]pyrimidin~~-2-~~yl)amino)propanenitrile~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	[[Category: ~~Unreleased Structures~~]]	+	</div>
-	[[Category: Appleton, B.A]]	+	<div class="pdbe-citations 6chl" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Pantetheine-phosphate adenylyltransferase]]
		+	[[Category: Appleton, B A]]
	[[Category: Mamo, M]]		[[Category: Mamo, M]]
		+	[[Category: Fbdd gram-negative antibacterial antibiotic]]
		+	[[Category: Ppat caad]]
		+	[[Category: Transferase transferase-antibiotic complex]]
		+	[[Category: Transferase-antibiotic complex]]

OCA at 05:05, 14 March 2018

OCA — Wed, 14 Mar 2018 05:05:54 GMT

←Older revision		Revision as of 05:05, 14 March 2018
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 6chl is ON HOLD	+	The entry 6chl is ON HOLD until Paper Publication

	Authors: Mamo, M., Appleton, B.A.		Authors: Mamo, M., Appleton, B.A.

OCA: Protected "6chl" [edit=sysop:move=sysop]

OCA — Wed, 28 Feb 2018 05:06:32 GMT

Protected "6chl" [edit=sysop:move=sysop]

←Older revision

Revision as of 05:06, 28 February 2018

OCA: New page: '''Unreleased structure''' The entry 6chl is ON HOLD Authors: Mamo, M., Appleton, B.A. Description: Phosphopantetheine adenylyltransferase (CoaD) in complex with (R)-3-(3-chlorophenyl)...

OCA — Wed, 28 Feb 2018 05:06:31 GMT

New page: '''Unreleased structure''' The entry 6chl is ON HOLD Authors: Mamo, M., Appleton, B.A. Description: Phosphopantetheine adenylyltransferase (CoaD) in complex with (R)-3-(3-chlorophenyl)...

New page

'''Unreleased structure'''

The entry 6chl is ON HOLD

Authors: Mamo, M., Appleton, B.A.

Description: Phosphopantetheine adenylyltransferase (CoaD) in complex with (R)-3-(3-chlorophenyl)-3-((5-methyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)amino)propanenitrile
[[Category: Unreleased Structures]]
[[Category: Appleton, B.A]]
[[Category: Mamo, M]]