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16 RNA Interaction with Small Ligands and Peptides

Joseph D. Puglisi, James R. Williamson


RNA is able to bind small molecule (MW <2000) ligands. These ligands can be drugs that bind to sites in biological RNAs, peptide fragments of larger proteins, or molecules for which RNA-binding sites (aptamers) have been selected by in vitro evolution. The RNAs that bind small molecules are modular, and the high local thermodynamic stability of RNA often assures stable folding of RNA domain fragments. Therefore, RNA–ligand interactions can often be studied using drastically reduced systems. RNA oligonucleotides can be produced in large quantities, and advances in NMR spectroscopy have allowed structure determination of RNA by NMR (Varani and Tinoco 1991; Chang and Varani 1997; Puglisi and Puglisi 1998). RNA–small molecule ligand complexes are particularly amenable to NMR structure determination.

This review focuses on the large number of NMR structures of RNA–ligand complexes that have been determined in recent years. These structures have revealed general themes for ligand recognition and have provided insights into the biological functions of RNAs. The binding and manipulation of small-molecule substrates was probably a central feature of the RNA World.

Three RNA aptamers whose structures have been determined at high resolution using multidimensional heteronuclear NMR (Feigon et al. 1996): ATP (Dieckmann et al. 1996; Jiang et al. 1996), FMN (Fan et al. 1996), and theophylline (Zimmermann et al. 1997), are shown in Figure 1. For comparison, the complex of HIV TAR with argininamide (Puglisi et al. 1992; Aboul-ela et al. 1995) is included as a small ligand...

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