engleski

Ribosome-Macrolide Interactions Monitored by NMR

One and two-dimensional NMR techniques have proven usefull in conformational analysis and structure-based inhibitor design. Macrolides are therapeutically important class of compounds that are effective inhibitors of bacterial protein biosynthesis. Macrolide antibiotics bind to the large 50S ribosomal subunit at or near the peptidyl transferase center and block the elongation of the peptide chain. Understanding the mechanism by which macrolides exert their activity is crucial for the design of novel molecules possessing bioactivity. However, the increasing resistance to ribosome-targeting antibiotics has become a global problem and much effort is now directed toward new and more potent classes of drugs to overcome resistance mechanisms. An effective approach to overcoming this problem is to understand the principles of how these drugs interact with the ribosome. Recently available crystal structures of some ribosome-macrolide complexes have thrown new light on the binding mechanisms. However, when analysing solid state structures of ribosome-macrolide complexes one should keep in mind the discrepancies between structures obtained for halophilic archeon H. marismortui and D. radiodurans. Therefore, important steps in the process of drug design should also include elucidation of the solution-state structures of free and bound ligand molecules since the structural features of the complex may not be exactly the same in solution and in the solid state. Here, an approach which combine NMR parameters such as spin-spin coupling constants, nOe and relaxation times coupled with molecular modelling is employed to study free conformations of macrolide antibiotics. Furthermore, an application of transferred nOe and STD NMR experiments provides information on the bound state conformation and binding epitopes. The knowledge gained from these studies can help in developing strategies aiming at design of potential inhibitors.

Ribosome; macrolide; NMR

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