4GI4

tRNA Guanine Transglycosylase in complex with disubstituted lin-benzoguanine inhibitor

4GI4 の概要

• エントリーDOI: 10.2210/pdb4gi4/pdb
• 関連するPDBエントリー: 3GC4 4GG9 4GH1 4GH3
• 分子名称: Queuine tRNA-ribosyltransferase, 6-amino-4-[2-(benzylamino)ethyl]-2-[(2-phenylethyl)amino]-1,7-dihydro-8H-imidazo[4,5-g]quinazolin-8-one, ZINC ION, ... (4 entities in total)
• 機能のキーワード: tim barrel glycosyltransferase, queuosine, biosynthesis, trna processing, trna, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Zymomonas mobilis subsp. mobilis
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 43444.65

構造登録者

Immekus, F.,Klebe, G. (登録日: 2012-08-08, 公開日: 2013-09-04, 最終更新日: 2025-11-12)

主引用文献

Barandun, L.J.,Immekus, F.,Kohler, P.C.,Ritschel, T.,Heine, A.,Orlando, P.,Klebe, G.,Diederich, F.
High-affinity inhibitors of Zymomonas mobilis tRNA-guanine transglycosylase through convergent optimization.
Acta Crystallogr.,Sect.D, 69:1798-1807, 2013

PubMed Abstract: The tRNA-modifying enzyme tRNA-guanine transglycosylase (TGT) has been recognized as a drug target for the treatment of the foodborne illness shigellosis. The active site of TGT consists of three pockets: the central guanine/preQ1 recognition site and the ribose-33 and ribose-34 pockets. In previous work, lin-benzoguanines and lin-benzohypoxanthines, which differ by the presence of an exocyclic NH2 group in the former and its absence in the latter, were used as central scaffolds that bind to the guanine/preQ1 recognition site and allow suitable functionalization along exit vectors targeting the two ribose pockets. The substituents for both of these two pockets have been optimized individually. Here, a series of bifunctionalized inhibitors that occupy both ribose pockets are reported for the first time. Dissociation constants Kd down to the picomolar range were measured for the bifunctionalized lin-benzoguanine-based ligands and Kd values in the nanomolar range were measured for the corresponding lin-benzohypoxanthine-based ligands. The binding mode of all inhibitors was elucidated by X-ray crystal structure analysis. A remarkable influence of the crystallization protocol on the solvation pattern in the solid state and the residual mobility of the bound ligands was observed.

PubMed: 23999303
DOI: 10.1107/S0907444913014509

実験手法

X-RAY DIFFRACTION (1.97 Å)