6chp: Difference between revisions
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==Phosphopantetheine adenylyltransferase (CoaD) in complex with methyl (R)-4-(3-(2-cyano-1-((5-methyl-1H-imidazo[4,5-b]pyridin-2-yl)amino)ethyl)benzyl)piperidine-1-carboxylate== | ==Phosphopantetheine adenylyltransferase (CoaD) in complex with methyl (R)-4-(3-(2-cyano-1-((5-methyl-1H-imidazo[4,5-b]pyridin-2-yl)amino)ethyl)benzyl)piperidine-1-carboxylate== | ||
<StructureSection load='6chp' size='340' side='right' caption='[[6chp]], [[Resolution|resolution]] 1.94Å' scene=''> | <StructureSection load='6chp' size='340' side='right'caption='[[6chp]], [[Resolution|resolution]] 1.94Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[6chp]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6CHP OCA]. For a <b>guided tour on the structure components</b> use [http:// | <table><tr><td colspan='2'>[[6chp]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6CHP OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6CHP FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=F0Y:methyl+4-[(3-{(1R)-2-cyano-1-[(5-methyl-3H-imidazo[4,5-b]pyridin-2-yl)amino]ethyl}phenyl)methyl]piperidine-1-carboxylate'>F0Y</scene>, <scene name='pdbligand=PG4:TETRAETHYLENE+GLYCOL'>PG4</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=F0Y:methyl+4-[(3-{(1R)-2-cyano-1-[(5-methyl-3H-imidazo[4,5-b]pyridin-2-yl)amino]ethyl}phenyl)methyl]piperidine-1-carboxylate'>F0Y</scene>, <scene name='pdbligand=PG4:TETRAETHYLENE+GLYCOL'>PG4</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:// | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6chp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6chp OCA], [http://pdbe.org/6chp PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6chp RCSB], [http://www.ebi.ac.uk/pdbsum/6chp PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6chp ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | == Function == | ||
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__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | |||
[[Category: Pantetheine-phosphate adenylyltransferase]] | [[Category: Pantetheine-phosphate adenylyltransferase]] | ||
[[Category: Appleton, B A]] | [[Category: Appleton, B A]] | ||
Revision as of 11:57, 11 November 2020
Phosphopantetheine adenylyltransferase (CoaD) in complex with methyl (R)-4-(3-(2-cyano-1-((5-methyl-1H-imidazo[4,5-b]pyridin-2-yl)amino)ethyl)benzyl)piperidine-1-carboxylatePhosphopantetheine adenylyltransferase (CoaD) in complex with methyl (R)-4-(3-(2-cyano-1-((5-methyl-1H-imidazo[4,5-b]pyridin-2-yl)amino)ethyl)benzyl)piperidine-1-carboxylate
Structural highlights
Function[COAD_ECOLI] Reversibly transfers an adenylyl group from ATP to 4'-phosphopantetheine, yielding dephospho-CoA (dPCoA) and pyrophosphate. Publication Abstract from PubMedIn 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[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)
OCA- Large Structures
- Pantetheine-phosphate adenylyltransferase
- Appleton, B A
- Mamo, M
- Dephospho-coa pyrophosphorylase pantetheine-phosphate adenylyltransferase ppat caad
- Fbdd gram-negati pantetheine-phosphate adenylyltransferaseve antibacterial antibiotic
- Transferase transferase-antibiotic complex
- Transferase-antibiotic complex