1N2V

Crystal Structure of TGT in complex with 2-Butyl-5,6-dihydro-1H-imidazo[4,5-d]pyridazine-4,7-dione

Summary for 1N2V

• Entry DOI: 10.2210/pdb1n2v/pdb
• Related: 1ENU 1PUD
• Descriptor: Queuine tRNA-ribosyltransferase, ZINC ION, 2-BUTYL-5,6-DIHYDRO-1H-IMIDAZO[4,5-D]PYRIDAZINE-4,7-DIONE, ... (4 entities in total)
• Functional Keywords: protein-ligand complex, transferase
• Biological source: Zymomonas mobilis
• Total number of polymer chains: 1
• Total formula weight: 43199.33

Authors

Brenk, R.,Naerum, L.,Graedler, U.,Gerber, H.-D.,Garcia, G.A.,Reuter, K.,Stubbs, M.T.,Klebe, G. (deposition date: 2002-10-24, release date: 2003-04-08, Last modification date: 2024-02-14)

Primary citation

Brenk, R.,Naerum, L.,Graedler, U.,Gerber, H.-D.,Garcia, G.A.,Reuter, K.,Stubbs, M.T.,Klebe, G.
Virtual screening for submicromolar leads of tRNA-guanine transglycosylase based on a new unexpected binding mode detected by crystal structure analysis
J.Med.Chem., 46:1133-1143, 2003

PubMed Abstract: Eubacterial tRNA-guanine transglycosylase (TGT) is involved in the hypermodification of cognate tRNAs, leading to the exchange of G34 by preQ1 at the wobble position in the anticodon loop. Mutation of the tgt gene in Shigella flexneri results in a significant loss of pathogenicity of the bacterium due to inefficient translation of a virulence protein mRNA. Herein, we describe the discovery of a ligand with an unexpected binding mode. On the basis of this binding mode, three slightly deviating pharmacophore hypotheses have been derived. Virtual screening based on this composite pharmacophore model retrieved a set of potential TGT inhibitors belonging to several compound classes. All nine tested inhibitors being representatives of these classes showed activity in the micromolar range, two of them even in the submicromolar range.

PubMed: 12646024
DOI: 10.1021/jm0209937

Experimental method

X-RAY DIFFRACTION (2.1 Å)