Synthetic ligands for PreQ1 riboswitches provide structural and mechanistic insights into targeting RNA tertiary structure

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...

Full description

Saved in:
Bibliographic Details
Published in:Nature communications 2019-04, Vol.10 (1), p.1501-1501, Article 1501
Main Authors: Connelly, Colleen M., Numata, Tomoyuki, Boer, Robert E., Moon, Michelle H., Sinniah, Ranu S., Barchi, Joseph J., Ferré-D’Amaré, Adrian R., Schneekloth, John S.
Format: Article
Language:English
Subjects:
101/47
631/45/500
631/45/535
631/92/507
631/92/613
Aptamers
Binding sites
Chemical fingerprinting
Crystallography
Gene expression
Humanities and Social Sciences
Ligands
multidisciplinary
Organic chemistry
Protein structure
Ribonucleic acid
Riboswitches
RNA
Science
Science (multidisciplinary)
Tertiary structure
Transcription termination
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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 PreQ 1 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. RNA sensors—Riboswitches—respond to the binding of small molecules ligands through structure modification. Here the authors identify synthetic small molecules that bind and regulate the activity of PreQ 1 Riboswitches despite having no obvious chemical similarity to the cognate ligand.
ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-019-09493-3