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Protein Science (2001), 10:2008-2016.
Copyright © 2001 The Protein Society

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

Xiayang Qiu1, Cheryl A. Janson1, Ward W. Smith1, Susan M. Green1, Patrick McDevitt1, Kyung Johanson1, Paul Carter2, Martin Hibbs2, Ceri Lewis2, Alison Chalker1, Andrew Fosberry2, Judith Lalonde1, John Berge2, Pamela Brown2, Catherine S.V. Houge-Frydrych2 and Richard L. Jarvest2

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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