Several metabolites regulate their own production by directly interacting with highly conserved regions of mRNA capable of forming a discrete tertiary structure. These regions of mRNA are called riboswitches, and more than 10 essential compounds have been shown to regulate their cellular levels in this manner. Several riboswitches are targeted by antibiotics, making them promising drug targets. Structural and biochemical studies on riboswitches revealed that the small-molecule ligands bind the RNA with high specificity and affinity. For example, riboswitches efficiently discern the biologically relevant form of these metabolites, e.g., the phosphorylated versus the non-phosphorylated form of riboflavin or the enzymati-cally active sulfonium configuration of S-adenosyl methionine (SAM). Crystal structures of several riboswitches, including the bacterial and the eukaryotic thiamine pyrophosphate (TPP)-specific riboswitches, uncovered that the bound ligands are deeply buried, far more so than typically observed for in vitro selected oligonucleotides or aptamers. Furthermore, the binding pockets of riboswitches form via a ligand-mediated induced-fit mechanism that involves the reorganization of RNA elements.
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