High-affinity inhibitors of Zymomonas mobilis tRNA-guanine transglycosylase through convergent optimization
| Autor: | Philipp C. Kohler, Andreas Heine, Tina Ritschel, Luzi Jakob Barandun, Gerhard Klebe, F. Immekus, Pierfrancesco Orlando, François Diederich |
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| Rok vydání: | 2013 |
| Předmět: |
chemistry.chemical_classification
Chemical and physical biology [NCMLS 7] Zymomonas Guanine biology Stereochemistry Active site General Medicine Crystal structure biology.organism_classification Crystallography X-Ray Zymomonas mobilis Binding Competitive Dissociation constant chemistry.chemical_compound Enzyme chemistry Structural Biology Transfer RNA Ribose biology.protein Pentosyltransferases Protein Binding |
| Zdroj: | Acta Crystallographica Section D-Biological Crystallography, 69, Pt 9, pp. 1798-807 Acta Crystallographica Section D-Biological Crystallography, 69, 1798-807 |
| ISSN: | 0907-4449 |
| DOI: | 10.1107/s0907444913014509 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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