Abstract
Riboswitches are naturally occurring RNA aptamers that regulate gene expression by binding to specific small molecules. Riboswitches control the expression of essential bacterial genes and are important models for RNA-small molecule recognition. Here, we report the discovery of a class of synthetic small molecules that bind to PreQ1 riboswitch aptamers. These molecules bind specifically and reversibly to the aptamers with high affinity and induce a conformational change. Furthermore, the ligands modulate riboswitch activity through transcriptional termination despite no obvious chemical similarity to the cognate ligand. X-ray crystallographic studies reveal that the ligands share a binding site with the cognate ligand but make different contacts. Finally, alteration of the chemical structure of the ligand causes changes in the mode of RNA binding and affects regulatory function. Thus, target- and structure-based approaches can be used to identify and understand the mechanism of synthetic ligands that bind to and regulate complex, folded RNAs.
Highlights
Riboswitches are naturally occurring RNA aptamers that regulate gene expression by binding to specific small molecules
Riboswitches act as regulators of gene expression through recognition of a small-molecule ligand that induces a conformational change in the RNA, thereby regulating downstream gene expression[12]
To identify drug-like small molecules that bind to the PreQ1 riboswitch, we used a small molecule microarray (SMM)-screening strategy[32,33,34,35,36,37,38,39,40]
Summary
Riboswitches are naturally occurring RNA aptamers that regulate gene expression by binding to specific small molecules. We report the discovery of a class of synthetic small molecules that bind to PreQ1 riboswitch aptamers These molecules bind and reversibly to the aptamers with high affinity and induce a conformational change. Alteration of the chemical structure of the ligand causes changes in the mode of RNA binding and affects regulatory function. Molecules recognized can range from nucleobases, cofactors, and amino acids to metal ions[13] These structured RNA elements have two domains, an aptamer domain that recognizes the cognate ligand through specific interactions, and an expression platform that changes conformation upon binding to modulate gene expression[12]. The role of Q is linked to the preservation of translational fidelity and aids reading of degenerate codons
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