6RKQ
Crystal Structure of TGT in complex with N2-methyl-8-(prop-1-yn-1-yl)-3H,7H,8H-imidazo[4,5-g]quinazoline-2,6-diamine
Summary for 6RKQ
| Entry DOI | 10.2210/pdb6rkq/pdb |
| Descriptor | Queuine tRNA-ribosyltransferase, ZINC ION, (8~{R})-~{N}2-methyl-8-prop-1-ynyl-7,8-dihydro-3~{H}-imidazo[4,5-g]quinazoline-2,6-diamine, ... (6 entities in total) |
| Functional Keywords | tgt, trna, guanine exchange enzyme, protein interface, transferase, transglycosylase |
| Biological source | Zymomonas mobilis subsp. mobilis (strain ATCC 31821 / ZM4 / CP4) |
| Total number of polymer chains | 1 |
| Total formula weight | 42253.41 |
| Authors | Hassaan, E.,Heine, A.,Klebe, G. (deposition date: 2019-04-30, release date: 2020-06-03, Last modification date: 2024-01-24) |
| Primary citation | 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 Cited by 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: 32515955DOI: 10.1021/acs.jmedchem.0c00115 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.665 Å) |
Structure validation
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