Conformational readout of RNA by small ligands
RNA molecules have highly versatile structures that can fold into myriad conformations, providing many potential pockets for binding small molecules. The increasing number of available RNA structures, in complex with proteins, small ligands and in free form, enables the design of new therapeutically useful RNA-binding ligands. Here we studied RNA ligand complexes from 10 RNA groups extracted from the protein data bank (PDB), including adaptive and non-adaptive complexes. We analyzed the chemical, physical, structural and conformational properties of binding pockets around the ligand. Comparing the properties of ligand-binding pockets to the properties of computed pockets extracted from all available RNA structures and RNA-protein interfaces, revealed that ligand-binding pockets, mainly the adaptive pockets, are characterized by unique properties, specifically enriched in rare conformations of the nucleobase and the sugar pucker. Further, we demonstrate that nucleotides possessing the rare conformations are preferentially involved in direct interactions with the ligand. Overall, based on our comprehensive analysis of RNA-ligand complexes, we suggest that the unique conformations adopted by RNA nucleotides play an important role in RNA recognition by small ligands. We term the recognition of a binding site by a ligand via the unique RNA conformations "RNA conformational readout." We propose that "conformational readout" is a general way by which RNA binding pockets are recognized and selected from an ensemble of different RNA states.
(A) Enrichment of structural properties in 33 representative structures of ligand binding pockets on RNA. Heatmap demonstrates over- and under- representations of the different structural properties in the binding pockets relative to background. The color scheme refers to the standardized score calculated against a background of computed pockets (calculated by the Solvent program). Scores were scaled to range from -1 to 1. Significant preferences of properties relative to the background of all RNA pockets are colored red (1) while blue denotes under-representation (-1). Numbers represent the index of the complex. (B) Hierarchical clustering of the 33 representative structures of RNA ligand complexes based on their structural properties. The colors of the dots represent different RNA groups (7SK SNRNA – bright green, Aptamer – red, DIS-HIV1 – pink, Duplex – brown, HIV1 Helix – azure, HCV IRES Domain IIa – gray, Riboswitch – yellow, Ribozyme – blue, TAR-purple, Splicing Regulatory – dark green).