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PDBsum entry 4nah

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protein ligands Protein-protein interface(s) links
Transferase/transferase inhibitor PDB id
4nah
Jmol
Contents
Protein chains
(+ 0 more) 159 a.a.
Ligands
AGS ×6
2VJ ×6
Waters ×78
PDB id:
4nah
Name: Transferase/transferase inhibitor
Title: Inhibitors of 4-phosphopanthetheine adenylyltransferase (ppa
Structure: Phosphopantetheine adenylyltransferase. Chain: a, b, c, d, e, f. Synonym: dephospho-coa pyrophosphorylase, pantetheine-phosp adenylyltransferase, ppat. Engineered: yes
Source: Staphylococcus aureus. Organism_taxid: 196620. Strain: mw2. Gene: coad, mw1007. Expressed in: escherichia coli. Expression_system_taxid: 562
Resolution:
2.38Å     R-factor:   0.220     R-free:   0.292
Authors: S.D.Lahiri
Key ref: B.L.de Jonge et al. (2013). Discovery of inhibitors of 4'-phosphopantetheine adenylyltransferase (PPAT) to validate PPAT as a target for antibacterial therapy. Antimicrob Agents Chemother, 57, 6005-6015. PubMed id: 24041904 DOI: 10.1128/AAC.01661-13
Date:
22-Oct-13     Release date:   12-Mar-14    
PROCHECK
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 Headers
 References

Protein chains
Pfam   ArchSchema ?
P63820  (COAD_STAAW) -  Phosphopantetheine adenylyltransferase
Seq:
Struc:
160 a.a.
159 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.2.7.7.3  - Pantetheine-phosphate adenylyltransferase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]

      Pathway:
Coenzyme A Biosynthesis (late stages)
      Reaction: ATP + pantetheine 4'-phosphate = diphosphate + 3'-dephospho-CoA
ATP
Bound ligand (Het Group name = AGS)
matches with 93.75% similarity
+ pantetheine 4'-phosphate
= diphosphate
+ 3'-dephospho-CoA
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     cytoplasm   1 term 
  Biological process     biosynthetic process   2 terms 
  Biochemical function     catalytic activity     6 terms  

 

 
    reference    
 
 
DOI no: 10.1128/AAC.01661-13 Antimicrob Agents Chemother 57:6005-6015 (2013)
PubMed id: 24041904  
 
 
Discovery of inhibitors of 4'-phosphopantetheine adenylyltransferase (PPAT) to validate PPAT as a target for antibacterial therapy.
B.L.de Jonge, G.K.Walkup, S.D.Lahiri, H.Huynh, G.Neckermann, L.Utley, T.J.Nash, J.Brock, M.San Martin, A.Kutschke, M.Johnstone, V.Laganas, L.Hajec, R.F.Gu, H.Ni, B.Chen, K.Hutchings, E.Holt, D.McKinney, N.Gao, S.Livchak, J.Thresher.
 
  ABSTRACT  
 
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.