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==Phosphopantetheine adenylyltransferase (CoaD) in complex with N-(2-(5-methoxy-1H-indol-3-yl)ethyl)pivalamide== | |||
<StructureSection load='6chm' size='340' side='right' caption='[[6chm]], [[Resolution|resolution]] 2.28Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6chm]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6CHM OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6CHM FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=F1V:N-[2-(5-methoxy-1H-indol-3-yl)ethyl]-2,2-dimethylpropanamide'>F1V</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=6chm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6chm OCA], [http://pdbe.org/6chm PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6chm RCSB], [http://www.ebi.ac.uk/pdbsum/6chm PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6chm 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. | |||
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> | |||
[[Category: | </div> | ||
[[Category: Appleton, B | <div class="pdbe-citations 6chm" style="background-color:#fffaf0;"></div> | ||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Pantetheine-phosphate adenylyltransferase]] | |||
[[Category: Appleton, B A]] | |||
[[Category: Mamo, M]] | [[Category: Mamo, M]] | ||
[[Category: Dephospho-coa pyrophosphorylase]] | |||
[[Category: Fbdd gram-negative antibacterial antibiotic]] | |||
[[Category: Ppat caad]] | |||
[[Category: Transferase transferase-antibiotic complex]] | |||
[[Category: Transferase-antibiotic complex]] | |||
Revision as of 08:59, 4 April 2018
Phosphopantetheine adenylyltransferase (CoaD) in complex with N-(2-(5-methoxy-1H-indol-3-yl)ethyl)pivalamidePhosphopantetheine adenylyltransferase (CoaD) in complex with N-(2-(5-methoxy-1H-indol-3-yl)ethyl)pivalamide
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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