Crystal structure of Staphylococcus aureus tyrosyl-tRNA synthetase in complex with a class of potent and specific inhibitors

SB-219383 and its analogues are a class of potent and specific inhibitors o f bacterial tyrosyl-tRNA synthetases. Crystal structures of these inhibitor s have been solved in complex with the tyrosyl-tRNA synthetase from Staphyl ococcus aureus, the bacterium that is largely responsible for hospital-acqu ired infections. The full-length enzyme yielded crystals that diffracted to 2.8 Angstrom resolution, but a truncated version of the enzyme allowed the resolution to be extended to 2.2 Angstrom. These inhibitors not only occup y the known substrate binding sites in unique ways, but also reveal a butyl binding pocket. It was reported that the Bacillus stearothermophilus TyrRS T51P mutant has much increased catalytic activity. The S. aureus enzyme ha ppens to have a proline at position 51. Therefore, our structures may contr ibute to the understanding of the catalytic mechanism and provide the struc tural basis for designing novel antimicrobial agents.