Crystal structure of Staphylococcus aureus tyrosyl‐tRNA synthetase in complex with a class of potent and specific inhibitors
Open Access
- 1 October 2001
- journal article
- Published by Wiley in Protein Science
- Vol. 10 (10), 2008-2016
- https://doi.org/10.1110/ps.18001
Abstract
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
This publication has 19 references indexed in Scilit:
- Potent synthetic inhibitors of tyrosyl tRNA synthetase derived from C-pyranosyl analogues of SB-219383Bioorganic & Medicinal Chemistry Letters, 2001
- The efficacy of intranasal mupirocin in the prevention of staphylococcal infections: a review of recent experienceJournal of Hospital Infection, 1994
- Partition of tRNA synthetases into two classes based on mutually exclusive sets of sequence motifsNature, 1990
- Structure of tyrosyl-tRNA synthetase refined at 2.3 Å resolution: Interaction of the enzyme with the tyrosyl adenylate intermediateJournal of Molecular Biology, 1989
- Reconstruction by site-directed mutagenesis of the transition state for the activation of tyrosine by the tyrosyl-tRNA synthetase: a mobile loop envelopes the transition state in an induced-fit mechanismBiochemistry, 1988
- Crystal structure of a deletion mutant of a tyrosyl-tRNA synthetase complexed with tyrosineJournal of Molecular Biology, 1987
- Structure of a mutant of tyrosyl-tRNA synthetase with enhanced catalytic propertiesNature, 1987
- Transition-state stabilization in the mechanism of tyrosyl-tRNA synthetase revealed by protein engineering.Proceedings of the National Academy of Sciences of the United States of America, 1985
- Demonstration of two active sites on a monomeric aminoacyl-tRNA synthetase. Possible roles of negative cooperativity and half-of-the-sites reactivity in oligomeric enzymesBiochemistry, 1975
- Crystallization and preliminary X-ray diffraction studies on tyrosyl-transfer RNA synthetase from Bacillus stearothermophilusJournal of Molecular Biology, 1973