6cck

Crystal structure of E.coli Phosphopantetheine Adenylyltransferase (PPAT/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)propanenitrileCrystal structure of E.coli Phosphopantetheine Adenylyltransferase (PPAT/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

Structural highlights 6cck is a 2 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: , , , Activity: Pantetheine-phosphate adenylyltransferase, with EC number 2.7.7.3 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [COAD_ECOLI] Reversibly transfers an adenylyl group from ATP to 4'-phosphopantetheine, yielding dephospho-CoA (dPCoA) and pyrophosphate. 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

spinqualitylabelsall models 6cck, resolution 1.61Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image