6chn: Difference between revisions

← Older edit Newer edit →

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 6chn is ON HOLD  until Paper Publication
+==Phosphopantetheine adenylyltransferase (CoaD) in complex with methyl (R)-4-(3-(2-cyano-1-((5-methyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)amino)ethyl)phenoxy)piperidine-1-carboxylate==
+<StructureSection load='6chn' size='340' side='right' caption='[[6chn]], [[Resolution|resolution]] 2.03&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[6chn]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6CHN OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6CHN FirstGlance]. <br>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=F1D:methyl+4-(3-{(1R)-2-cyano-1-[(5-methyl-7-oxo-6,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)amino]ethyl}phenoxy)piperidine-1-carboxylate'>F1D</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</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='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=6chn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6chn OCA], [http://pdbe.org/6chn PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6chn RCSB], [http://www.ebi.ac.uk/pdbsum/6chn PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6chn 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 methyl (R)-4-(3-(2-cyano-1-((5-methyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)amino)ethyl)phenoxy)piperidine-1-carboxylate
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
-[[Category: Appleton, B.A]]
+<div class="pdbe-citations 6chn" style="background-color:#fffaf0;"></div>
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Pantetheine-phosphate adenylyltransferase]]
+[[Category: Appleton, B A]]
 [[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]]