6ccs - Revision history

OCA at 14:27, 13 March 2024

OCA — Wed, 13 Mar 2024 14:27:49 GMT

←Older revision		Revision as of 14:27, 13 March 2024
Line 3:		Line 3:
	<StructureSection load='6ccs' size='340' side='right'caption='[[6ccs]], [[Resolution\|resolution]] 2.06Å' scene=''>		<StructureSection load='6ccs' size='340' side='right'caption='[[6ccs]], [[Resolution\|resolution]] 2.06Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[6ccs]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6CCS OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://proteopedia.org/fgij/fg.htm?mol=6CCS FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[6ccs]] 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=6CCS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6CCS FirstGlance]. <br>
-	</td></tr><tr id='~~ligand~~'><td class="sblockLbl"><b>[[~~Ligand~~\|~~Ligands~~:]]</b></td><td class="sblockDat" id="~~ligandDat~~">~~<scene name='pdbligand=EXD:2~~-~~(trifluoromethyl)-1H-benzimidazol-7-ol'>EXD</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]] 2.06Å</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=EXD:2-(trifluoromethyl)-1H-benzimidazol-7-ol'>EXD</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=6ccs FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ccs OCA], [~~http~~://pdbe.org/6ccs PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=6ccs RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/6ccs PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=6ccs 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=6ccs FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ccs OCA], [https://pdbe.org/6ccs PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6ccs RCSB], [https://www.ebi.ac.uk/pdbsum/6ccs PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6ccs 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 ==~~	+
-	The discovery and development of new antibiotics capable of curing infections due to multidrug-resistant and pandrug-resistant Gram-negative bacteria is a major challenge with fundamental importance to our global healthcare system. Part of our broad program at Novartis to address this urgent, unmet need includes the search for new agents that inhibit novel bacterial targets. Here we report the discovery and hit-to-lead optimization of new inhibitors of phosphopantetheine adenylyltransferase (PPAT) from Gram-negative bacteria. Utilizing a fragment-based screening approach, we discovered a number of unique scaffolds capable of interacting with the pantetheine site of E. coli PPAT and inhibiting enzymatic activity, including triazolopyrimidinone 6. Structure-based optimization resulted in the identification of two lead compounds as selective, small molecule inhibitors of bacterial PPAT: triazolopyrimidinone 53 and azabenzimidazole 54 efficiently inhibited E. coli and P. aeruginosa PPAT and displayed modest cellular potency against the efflux-deficient E. coli DeltatolC mutant strain.	+
-		+
-	Fragment-Based Drug Discovery of Inhibitors of Phosphopantetheine Adenylyltransferase from Gram-Negative Bacteria.,Moreau RJ, Skepper CK, Appleton BA, Blechschmidt A, Balibar CJ, Benton BM, Drumm JE, Feng BY, Geng M, Li C, Lindvall MK, Lingel A, Lu Y, Mamo M, Mergo W, Polyakov V, Smith TM, Takeoka K, Uehara K, Wang L, Wei JR, Weiss AH, Xie L, Xu W, Zhang Q, de Vicente J J Med Chem. 2018 Mar 2. doi: 10.1021/acs.jmedchem.7b01691. PMID:29498517<ref>PMID:29498517</ref>	+
-		+
-	~~From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>~~	+
-	~~</div>~~	+
-	~~<div class="pdbe-citations 6ccs" 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: Ppat coad fbdd phosphopantetheine adenylyltransferase gram-negative antibacterial antibiotic]]~~	+
-	~~[[Category: Transferase]]~~	+
-	~~[[Category: Transferase-antibiotic complex~~]]	+

OCA at 08:56, 11 November 2020

OCA — Wed, 11 Nov 2020 08:56:29 GMT

←Older revision		Revision as of 08:56, 11 November 2020
Line 1:		Line 1:

	==Crystal structure of E.coli Phosphopantetheine Adenylyltransferase (PPAT/CoaD) in complex with 2-(trifluoromethyl)-1H-benzo[d]imidazol-4-ol==		==Crystal structure of E.coli Phosphopantetheine Adenylyltransferase (PPAT/CoaD) in complex with 2-(trifluoromethyl)-1H-benzo[d]imidazol-4-ol==
-	<StructureSection load='6ccs' size='340' side='right' caption='[[6ccs]], [[Resolution\|resolution]] 2.06Å' scene=''>	+	<StructureSection load='6ccs' size='340' side='right'caption='[[6ccs]], [[Resolution\|resolution]] 2.06Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[6ccs]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6CCS OCA]. For a <b>guided tour on the structure components</b> use [http://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=6CCS FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[6ccs]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6CCS OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6CCS FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EXD:2-(trifluoromethyl)-1H-benzimidazol-7-ol'>EXD</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=EXD:2-(trifluoromethyl)-1H-benzimidazol-7-ol'>EXD</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=6ccs FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ccs OCA], [http://pdbe.org/6ccs PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6ccs RCSB], [http://www.ebi.ac.uk/pdbsum/6ccs PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6ccs 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=6ccs FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ccs OCA], [http://pdbe.org/6ccs PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6ccs RCSB], [http://www.ebi.ac.uk/pdbsum/6ccs PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6ccs 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 06:32, 14 March 2018

OCA — Wed, 14 Mar 2018 06:32:19 GMT

←Older revision		Revision as of 06:32, 14 March 2018
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 6ccs is ~~ON HOLD~~	+	==Crystal structure of E.coli Phosphopantetheine Adenylyltransferase (PPAT/CoaD) in complex with 2-(trifluoromethyl)-1H-benzo[d]imidazol-4-ol==
		+	<StructureSection load='6ccs' size='340' side='right' caption='[[6ccs]], [[Resolution\|resolution]] 2.06Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[6ccs]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6CCS OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6CCS FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EXD:2-(trifluoromethyl)-1H-benzimidazol-7-ol'>EXD</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=6ccs FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ccs OCA], [http://pdbe.org/6ccs PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6ccs RCSB], [http://www.ebi.ac.uk/pdbsum/6ccs PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6ccs 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 ==
		+	The discovery and development of new antibiotics capable of curing infections due to multidrug-resistant and pandrug-resistant Gram-negative bacteria is a major challenge with fundamental importance to our global healthcare system. Part of our broad program at Novartis to address this urgent, unmet need includes the search for new agents that inhibit novel bacterial targets. Here we report the discovery and hit-to-lead optimization of new inhibitors of phosphopantetheine adenylyltransferase (PPAT) from Gram-negative bacteria. Utilizing a fragment-based screening approach, we discovered a number of unique scaffolds capable of interacting with the pantetheine site of E. coli PPAT and inhibiting enzymatic activity, including triazolopyrimidinone 6. Structure-based optimization resulted in the identification of two lead compounds as selective, small molecule inhibitors of bacterial PPAT: triazolopyrimidinone 53 and azabenzimidazole 54 efficiently inhibited E. coli and P. aeruginosa PPAT and displayed modest cellular potency against the efflux-deficient E. coli DeltatolC mutant strain.

-	~~Authors: Mamo, M~~., Appleton, B.A.	+	Fragment-Based Drug Discovery of Inhibitors of Phosphopantetheine Adenylyltransferase from Gram-Negative Bacteria.,Moreau RJ, Skepper CK, Appleton BA, Blechschmidt A, Balibar CJ, Benton BM, Drumm JE, Feng BY, Geng M, Li C, Lindvall MK, Lingel A, Lu Y, Mamo M, Mergo W, Polyakov V, Smith TM, Takeoka K, Uehara K, Wang L, Wei JR, Weiss AH, Xie L, Xu W, Zhang Q, de Vicente J J Med Chem. 2018 Mar 2. doi: 10.1021/acs.jmedchem.7b01691. PMID:29498517<ref>PMID:29498517</ref>

-	~~Description: Crystal structure~~ of E.~~coli Phosphopantetheine Adenylyltransferase (PPAT~~/~~CoaD) in complex with 2-(trifluoromethyl)~~-1H-~~benzo[d]imidazol-4-ol~~	+	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 6ccs" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Pantetheine-phosphate adenylyltransferase]]
		+	[[Category: Appleton, B A]]
	[[Category: Mamo, M]]		[[Category: Mamo, M]]
		+	[[Category: Ppat coad fbdd phosphopantetheine adenylyltransferase gram-negative antibacterial antibiotic]]
		+	[[Category: Transferase]]
		+	[[Category: Transferase-antibiotic complex]]

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

OCA — Thu, 15 Feb 2018 05:23:23 GMT

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

←Older revision

Revision as of 05:23, 15 February 2018

OCA: New page: '''Unreleased structure''' The entry 6ccs is ON HOLD Authors: Mamo, M., Appleton, B.A. Description: Crystal structure of E.coli Phosphopantetheine Adenylyltransferase (PPAT/CoaD) in co...

OCA — Thu, 15 Feb 2018 05:23:22 GMT

New page: '''Unreleased structure''' The entry 6ccs is ON HOLD Authors: Mamo, M., Appleton, B.A. Description: Crystal structure of E.coli Phosphopantetheine Adenylyltransferase (PPAT/CoaD) in co...

New page

'''Unreleased structure'''

The entry 6ccs is ON HOLD

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

Description: Crystal structure of E.coli Phosphopantetheine Adenylyltransferase (PPAT/CoaD) in complex with 2-(trifluoromethyl)-1H-benzo[d]imidazol-4-ol
[[Category: Unreleased Structures]]
[[Category: Appleton, B.A]]
[[Category: Mamo, M]]