title: Crystal structure of Staphylococcus aureus tyrosyl-tRNA synthetase in complex with a class of potent and specific inhibitors.
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 A resolution, but a truncated version of the enzyme allowed the resolution to be extended to 2.2 A. 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.
authors.affiliation: GlaxoSmithKline, King of Prussia, Pennsylvania 19406, USA. xiayang_qui-1@sbphrd.com
authors.forename: X
authors.initials: X
authors.lastname: Qiu
authors.forename: C A
authors.initials: CA
authors.lastname: Janson
authors.forename: W W
authors.initials: WW
authors.lastname: Smith
authors.forename: S M
authors.initials: SM
authors.lastname: Green
authors.forename: P
authors.initials: P
authors.lastname: McDevitt
authors.forename: K
authors.initials: K
authors.lastname: Johanson
authors.forename: P
authors.initials: P
authors.lastname: Carter
authors.forename: M
authors.initials: M
authors.lastname: Hibbs
authors.forename: C
authors.initials: C
authors.lastname: Lewis
authors.forename: A
authors.initials: A
authors.lastname: Chalker
authors.forename: A
authors.initials: A
authors.lastname: Fosberry
authors.forename: J
authors.initials: J
authors.lastname: Lalonde
authors.forename: J
authors.initials: J
authors.lastname: Berge
authors.forename: P
authors.initials: P
authors.lastname: Brown
authors.forename: C S
authors.initials: CS
authors.lastname: Houge-Frydrych
authors.forename: R L
authors.initials: RL
authors.lastname: Jarvest
mesh_terms: D000595:Amino Acid Sequence; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry / Q000494:pharmacology; D003460:Crystallization; D018360:Crystallography, X-Ray; D004151:Dipeptides / Q000737:chemistry / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D005663:Furans / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology; D011487:Protein Conformation; D017386:Sequence Homology, Amino Acid; D013211:Staphylococcus aureus / Q000201:enzymology*; D014448:Tyrosine-tRNA Ligase / Q000037:antagonists & inhibitors / Q000737:chemistry*
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D004151:Dipeptides; D004791:Enzyme Inhibitors; D005663:Furans; D010880:Piperidines; C410784:SB 219383; C439613:SB 239629; C439614:SB 243545; D014448:Tyrosine-tRNA Ligase