6RKT

Crystal Structure of TGT in complex with N2-methyl-1H,7H,8H-imidazo[4,5-g]quinazoline-2,6-diamine

6RKT の概要

• エントリーDOI: 10.2210/pdb6rkt/pdb
• 分子名称: Queuine tRNA-ribosyltransferase, GLYCEROL, DIMETHYL SULFOXIDE, ... (6 entities in total)
• 機能のキーワード: tgt, trna, guanine exchange enzyme, protein interface, transferase, transglycosylase
• 由来する生物種: Zymomonas mobilis
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 42215.36

構造登録者

Hassaan, E.,Heine, A.,Klebe, G. (登録日: 2019-04-30, 公開日: 2020-06-03, 最終更新日: 2024-01-24)

主引用文献

Hassaan, E.,Hohn, C.,Ehrmann, F.R.,Goetzke, F.W.,Movsisyan, L.,Hufner-Wulsdorf, T.,Sebastiani, M.,Hartsch, A.,Reuter, K.,Diederich, F.,Klebe, G.
Fragment Screening Hit Draws Attention to a Novel Transient Pocket Adjacent to the Recognition Site of the tRNA-Modifying Enzyme TGT.
J.Med.Chem., 63:6802-6820, 2020

PubMed Abstract: Fragment-based lead discovery was applied to tRNA-guanine transglycosylase, an enzyme modifying post-transcriptionally tRNAs in , the causative agent of shigellosis. TGT inhibition prevents translation of 's virulence factor VirF, hence reducing pathogenicity. One discovered fragment opens a transient subpocket in the preQ-recognition site by pushing back an aspartate residue. This step is associated with reorganization of further amino acids structurally transforming a loop adjacent to the recognition site by duplicating the volume of the preQ-recognition pocket. We synthesized 6-carboxamido-, 6-hydrazido-, and 4-guanidino-benzimidazoles to target the opened pocket, including a dihydro-imidazoquinazoline with a propyn-1-yl exit vector pointing into the transient pocket and displacing a conserved water network. MD simulations and hydration-site analysis suggest water displacement to contribute favorably to ligand binding. A cysteine residue, exclusively present in bacterial TGTs, serves as gatekeeper of the transient subpocket. It becomes accessible upon pocket opening for selective covalent attachment of electrophilic ligands in eubacterial TGTs.

PubMed: 32515955
DOI: 10.1021/acs.jmedchem.0c00115

実験手法

X-RAY DIFFRACTION (1.746 Å)