B12 cofactors directly stabilize an mRNA regulatory switch

The crystal structures of two different cobalamin (vitamin B 12 )-binding riboswitches are determined; the structures reveal how cobalamin facilitates interdomain interactions to regulate gene expression. An alternative structure for riboswitches Small metabolites and ligands can affect gene expression by binding to a structured part of an RNA known as a riboswitch. Although the structures of many riboswitch receptor domains have been solved, the complete riboswitch structure with regulatory domain had not been determined. Robert Batey and colleagues have now solved the structure of two different cobalamin (vitamin B 12 ) riboswitches that include the downstream regulatory domain. Ligand recognition occurs largely as a result of shape complementarity, rather than the more typical hydrogen bonding. Structures of riboswitch receptor domains bound to their effector have shown how messenger RNAs recognize diverse small molecules, but mechanistic details linking the structures to the regulation of gene expression remain elusive 1 , 2 . To address this, here we solve crystal structures of two different classes of cobalamin (vitamin B 12 )-binding riboswitches that include the structural switch of the downstream regulatory domain. These classes share a common cobalamin-binding core, but use distinct peripheral extensions to recognize different B 12 derivatives. In each case, recognition is accomplished through shape complementarity between the RNA and cobalamin, with relatively few hydrogen bonding interactions that typically govern RNA–small molecule recognition. We show that a composite cobalamin–RNA scaffold stabilizes an unusual long-range intramolecular kissing-loop interaction that controls mRNA expression. This is the first, to our knowledge, riboswitch crystal structure detailing how the receptor and regulatory domains communicate in a ligand-dependent fashion to regulate mRNA expression.