A new target for shigellosis: rational design and crystallographic studies of inhibitors of tRNA-guanine transglycosylase.
Eubacterial tRNA-guanine transglycosylase (TGT) is involved in the hyper-modification of cognate tRNAs leading to the exchange of G34 at the wobble position in the anticodon loop by preQ1 (2-amino-5-(aminomethyl)pyrrolo[2,3-d]pyrimidin-4(3H)-one) as part of the biosynthesis of queuine (Q). Mutation of the tgt gene in Shigella flexneri results in a significant loss of pathogenicity of the bacterium, revealing TGT as a new target for the design of potent drugs against Shigellosis. The X-ray structure of Zymomonas mobilis TGT in complex with preQ1 was used to search for new putative inhibitors with the computer program LUDI. An initial screen of the Available Chemical Directory, a database compiled from commercially available compounds, suggested several hits. Of these, 4-aminophthalhydrazide (APH) showed an inhibition constant in the low micromolar range. The 1.95 A crystal structure of APH in complex with Z. mobilis TGT served as a starting point for further modification of this initial lead.
Grädler
U
U
Institut für Pharmazeutische Chemie, Marbacher Weg 6, Philipps-Universität Marburg, 35032, Germany.
Gerber
H D
HD
Goodenough-Lashua
D M
DM
Garcia
G A
GA
Ficner
R
R
Reuter
K
K
Stubbs
M T
MT
Klebe
G
G
D001665:Binding Sites; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D019992:Databases as Topic; D015195:Drug Design; D004405:Dysentery, Bacillary / Q000188:drug therapy* / Q000382:microbiology; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D006147:Guanine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D007700:Kinetics; D008958:Models, Molecular; D015394:Molecular Structure; D010430:Pentosyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010793:Phthalazines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011744:Pyrimidinones / Q000737:chemistry / Q000378:metabolism; D011758:Pyrroles / Q000737:chemistry / Q000378:metabolism; D012763:Shigella flexneri / Q000187:drug effects / Q000201:enzymology*; D012984:Software; D055672:Static Electricity; D013816:Thermodynamics; D017355:Zymomonas / Q000201:enzymology
C422703:4-aminophthalhydrazide; C096876:7-(aminomethyl)-7-deazaguanine; D004791:Enzyme Inhibitors; D010793:Phthalazines; D011744:Pyrimidinones; D011758:Pyrroles; D006147:Guanine; C019549:queuine; D010430:Pentosyltransferases; C020837:queuine tRNA-ribosyltransferase