A Case Study: Structure-Based Inhibitor Design for tRNA-Guanine Transglycosylase

A case study should be considered before the numerous application examples are presented in the last part of this book. Using the example of the tRNA-modifying enzyme tRNA-guanine transglycosylase (TGT), the possibilities for inhibitor design presented in the last chapter are applied. In particular, the advantage of the iterative use of multiple cycles of structure-based design techniques will be highlighted. The example references work done by François Diederich’s research group at ETH Zurich, as well as work done by the author’s research group at Marburg University. The selected target, TGT, plays an important role in the pathogenicity of Shigella, a Gram-negative bacterium that infects the intestine and causes shigellosis. The enzyme catalyzes the complete nucleobase exchange of a specific guanine for the modified base preQ1 at the wobble position of selected tRNA molecules. The enzyme is only functional as a homodimer and forms a 2:1 complex with the substrate tRNA. Several design concepts for the inhibition of the enzyme have emerged: (i) inhibition of the active site by potent inhibitors; (ii) disruption of homodimer formation by active site inhibitors that perturb the interface contact surface with long, spike-like substituents; (iii) inhibitors that induce and stabilize the formation of a second, twisted and functionally incompetent homodimer; (iv) small ligands that fix a loop in the contact surface in a geometry that blocks the formation of the original homodimer; (v) filling a transient pocket with inhibitors that irreversibly bind to the thiol group of a cysteine residue present only in the bacterial enzymes. https://sn.pub/ya1k72