4nat

Inhibitors of 4-Phosphopanthetheine AdenylyltransferaseInhibitors of 4-Phosphopanthetheine Adenylyltransferase

Structural highlights 4nat is a 3 chain structure with sequence from Staphylococcus aureus subsp. aureus MW2. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: , , Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function COAD_STAAW Reversibly transfers an adenylyl group from ATP to 4'-phosphopantetheine, yielding dephospho-CoA (dPCoA) and pyrophosphate (By similarity). Publication Abstract from PubMed Inhibitors of 4'-phosphopantetheine adenylyltransferase (PPAT) were identified through high-throughput screening of the AstraZeneca compound library. One series, cycloalkyl pyrimidines, showed inhibition of PPAT isozymes from several species, with the most potent inhibition of enzymes from Gram-positive species. Mode-of-inhibition studies with Streptococcus pneumoniae and Staphylococcus aureus PPAT demonstrated representatives of this series to be reversible inhibitors competitive with phosphopantetheine and uncompetitive with ATP, binding to the enzyme-ATP complex. The potency of this series was optimized using structure-based design, and inhibition of cell growth of Gram-positive species was achieved. Mode-of-action studies, using generation of resistant mutants with targeted sequencing as well as constructs that overexpress PPAT, demonstrated that growth suppression was due to inhibition of PPAT. An effect on bacterial burden was demonstrated in mouse lung and thigh infection models, but further optimization of dosing requirements and compound properties is needed before these compounds can be considered for progress into clinical development. These studies validated PPAT as a novel target for antibacterial therapy. Discovery of inhibitors of 4'-phosphopantetheine adenylyltransferase (PPAT) to validate PPAT as a target for antibacterial therapy.,de Jonge BL, Walkup GK, Lahiri SD, Huynh H, Neckermann G, Utley L, Nash TJ, Brock J, San Martin M, Kutschke A, Johnstone M, Laganas V, Hajec L, Gu RF, Ni H, Chen B, Hutchings K, Holt E, McKinney D, Gao N, Livchak S, Thresher J Antimicrob Agents Chemother. 2013 Dec;57(12):6005-15. doi: 10.1128/AAC.01661-13. , Epub 2013 Sep 16. PMID:24041904 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

spinqualitylabelsall models 4nat, resolution 1.72Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image