Crystal structure of Staphylococcus aureus tyrosyl-tRNA synthetase in complex with a class of potent and specific inhibitors.
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.
Qiu
X
X
GlaxoSmithKline, King of Prussia, Pennsylvania 19406, USA. xiayang_qui-1@sbphrd.com
Janson
C A
CA
Smith
W W
WW
Green
S M
SM
McDevitt
P
P
Johanson
K
K
Carter
P
P
Hibbs
M
M
Lewis
C
C
Chalker
A
A
Fosberry
A
A
Lalonde
J
J
Berge
J
J
Brown
P
P
Houge-Frydrych
C S
CS
Jarvest
R L
RL
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*
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