Abstract

The microRNAs are non-coding RNAs which post-transcriptionally regulate the expression of a majority of eukaryotic genes, and whose dysregulation is a driver of many human diseases. Here we report the discovery of a very slow (0.1 sec) conformational rearrangement at the Dicer cleavage site of pre-miR-21 which regulates the relative concentration of readily processed and inefficiently processed structural states. We show this dynamic switch is affected by single nucleotide mutations and can be biased by small molecule and peptide ligands, which can direct the microRNA to occupy the inefficiently processed state and reduce processing efficiency. This result reveals a new mechanism of RNA regulation and suggests a chemical approach to suppressing or activating pathogenic microRNAs by selective stabilization of the unprocessed or processed state.