Structural insights into metabolite‐sensing mRNAs

Abstract

Riboswitches are structured elements found in the 5′‐untranslated regions of mRNAs that specifically bind small molecule metabolites to regulate gene expression in a cis‐fashion. These riboregulatory elements typically contain two domains: an aptamer domain that specifically recognizes and binds a ligand and an expression platform that directs expression of the mRNA at the transcriptional or translational level. Our laboratory has solved the X‐ray crystal structures of the aptamer domains of the purine and two S‐adenosylmethionine responsive riboswitches in complex with their cognate ligands, revealing complex tertiary architectures that scaffold the ligand‐binding pocket. In each case, almost all of the functional groups of the ligand are directly or indirectly read by the RNA resulting in their extremely high specificity. To complement these bounds structures, we have used biochemical and structural methods to reveal the nature of the unligand form of these aptamer domains, illuminating aspects of their ligand‐dependent folding. Regulation is achieved through a series of ligand‐induced tertiary structural changes in the RNA that serve to stabilize a helix that forms part of a secondary structural switch with the expression platform.