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

• Published in: Protein science Vol. 10; no. 10; pp. 2008 - 2016
• Main Authors: Qiu, Xiayang, Janson, Cheryl A., Smith, Ward W., Green, Susan M., McDevitt, Patrick, Johanson, Kyung, Carter, Paul, Hibbs, Martin, Lewis, Ceri, Chalker, Alison, Fosberry, Andrew, Lalonde, Judith, Berge, John, Brown, Pamela, Houge‐Frydrych, Catherine S.V., Jarvest, Richard L.
• Format: Journal Article
• Language: English
• Published: Bristol Cold Spring Harbor Laboratory Press 01.10.2001
• Subjects: Amino Acid Sequence; Bridged Bicyclo Compounds, Heterocyclic - chemistry; Bridged Bicyclo Compounds, Heterocyclic - pharmacology; bsTyrRS, Bacillus stearothermophilus TyrRS; bsTyrRStr, C‐terminal domain truncated bsTyrRS; Crystallization; Crystallography, X-Ray; Dipeptides - chemistry; Dipeptides - pharmacology; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Furans - chemistry; Furans - pharmacology; Models, Molecular; Molecular Sequence Data; Piperidines - chemistry; Piperidines - pharmacology; Protein Conformation; Sequence Homology, Amino Acid; Staphylococcus aureus; Staphylococcus aureus - enzymology; structure‐based drug design; truncation; Tyrosine-tRNA Ligase - antagonists & inhibitors; Tyrosine-tRNA Ligase - chemistry; Tyrosyl‐tRNA synthase; TyrRS, tyrosyl‐tRNA synthetase; YRS, Staphylococcus aureus tyrosyl‐tRNA synthetase; YRStr, C‐terminal domain truncated YRS
• ISSN: 0961-8368; 1469-896X
• DOI: 10.1110/ps.18001

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.