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

¹ GlaxoSmithKline, King of Prussia, Pennsylvania 19406, USA
² GlaxoSmithKline, Harlow, Essex CM19 5AW, UK

Reprint requests to: Xiayang Qiu, Mail Code UE0447, GlaxoSmithKline, King of Prussia, Pennsylvania 19406, USA; e-mail: xiayang_qiu-1{at}sbphrd.com; fax: (610) 270–4091.

SB-219383 and its analogues are a class of potent and specific inhibitors of bacterial tyrosyl-tRNA synthetases. Crystal structures of these inhibitors have been solved in complex with the tyrosyl-tRNA synthetase from Staphylococcus aureus, the bacterium that is largely responsible for hospital-acquired infections. The full-length enzyme yielded crystals that diffracted to 2.8 Å resolution, but a truncated version of the enzyme allowed the resolution to be extended to 2.2 Å. These inhibitors not only occupy 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 happens to have a proline at position 51. Therefore, our structures may contribute to the understanding of the catalytic mechanism and provide the structural basis for designing novel antimicrobial agents.

Keywords: Tyrosyl-tRNA synthase; structure-based drug design; truncation; Staphylococcus aureus

Abbreviations: TyrRS, tyrosyl-tRNA synthetase • bsTyrRS, Bacillus stearothermophilus TyrRS • YRS, Staphylococcus aureus tyrosyl-tRNA synthetase • YRStr, C-terminal domain truncated YRS • bsTyrRStr, C-terminal domain truncated bsTyrRS

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