4P75: Phers In Complex With Compound 4a

The antimicrobial activity of phenyl-thiazolylurea-sulfonamides against Staphylococcus aureus PheRS are dependent upon phenylalanine levels in the extracellular fluids. Inhibitor efficacy in animal models of infection is substantially diminished by dietary phenylalanine intake, thereby reducing the perceived clinical utility of this inhibitor class. The search for novel antibacterial compounds against Gram-negative pathogens led to a re-evaluation of this phenomenon, which is shown here to be unique to S. aureus. Inhibition of macromolecular syntheses and characterization of novel resistance mutations in Escherichia coli demonstrate that antimicrobial activity of phenyl-thiazolylurea-sulfonamides is mediated by PheRS inhibition, validating this enzyme as a viable drug discovery target for Gram-negative pathogens. A search for novel inhibitors of PheRS yielded three novel chemical starting points. NMR studies were used to confirm direct target engagement for phenylalanine-competitive hits. The crystallographic structure of Pseudomonas aeruginosa PheRS defined the binding modes of these hits and revealed an auxiliary hydrophobic pocket that is positioned adjacent to the phenylalanine binding site. Three viable inhibitor-resistant mutants were mapped to this pocket, suggesting that this region is a potential liability for drug discovery.
PDB ID: 4P75Download
MMDB ID: 121026
PDB Deposition Date: 2014/3/25
Updated in MMDB: 2015/10
Experimental Method:
x-ray diffraction
Resolution: 2.96  Å
Source Organism:
Similar Structures:
Biological Unit for 4P75: tetrameric; determined by author and by software (PISA)
Molecular Components in 4P75
Label Count Molecule
Proteins (4 molecules)
Phenylalanine--trna Ligase Beta Subunit(Gene symbol: pheT)
Molecule annotation
Phenylalanine--trna Ligase Alpha Subunit(Gene symbol: pheS)
Molecule annotation
Chemicals (2 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB