Chapter category: RNA

Switchable RNA Motifs As Drug Targets

This chapter appears in the following book:

Nucleic Acid Switches and Sensors

Edited by: Scott K. Silverman
ISBN: 0-387-37491-4
» Get more information about this book at landesbioscience.com «

Chapter authors:
Eric Westhof, Boris François and Quentin Vicens

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RNA molecules are highly negatively charged polymers that form intricate three-dimensional assemblies involving recurrent structural motifs. Therefore, in order to understand the molecular recognition of RNA, one of the key points to address is how RNA can be a specific target of natural or artificial antibiotics and drugs that are generally positively charged. Crystal structures of complexes between ribosomal particles from bacteria and antibiotics have pinned down very precisely the discrete binding sites of several classes of antibiotics that inhibit protein synthesis. These structures have unambiguously demonstrated that ribosomal RNAs, rather than ribosomal proteins, are overwhelmingly targeted. The comparative analyses of various aminoglycoside antibiotics bound to the same aminoacyl-transfer RNA (tRNA) decoding site (A site) have been used to decipher the contribution of each functional group to the RNA-aminoglycoside complex formation. In addition, various biochemical and microbiological data as well as some resistance and toxicity mechanisms could be rationalized at the molecular level. It was demonstrated that the binding of the aminoglycosides locks the A site into a conformation mimicking that adopted in presence of the cognate tRNA-codon association, thereby provoking a loss in translation fidelity by shunting a natural molecular switch. Similarly, although very high specificity might be difficult to achieve with oppositely charged molecules, targeting motifs that undergo dynamic exchange between alternative conformations (molecular switches) should improve the biological activity of antibacterial compounds.

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Chapter category: RNA

Switchable RNA Motifs As Drug Targets

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