2025/04/22 by Seth D. Veenbaas, Jordan T. Koehn, Patrick S. Irving +2 · 1 voice
Biochemistry, Genetics and Molecular Biology · #RNA Research and Splicing #RNA and protein synthesis mechanisms #RNA modifications and cancer
paper · doi:10.1073/pnas.2422346122
openalex publication_date 2025/04/22 · openalex created_date 2025/10/10 · openalex updated_date 2026/08/04
RNAs are critical regulators of gene expression, and their functions are often mediated by complex secondary and tertiary structures. Structured regions in RNA can selectively interact with small molecules—via well-defined ligand-binding pockets—to modulate the regulatory repertoire of an RNA. The broad potential to modulate biological function intentionally via RNA–ligand interactions remains unrealized, however, due to challenges in identifying compact RNA motifs with the ability to bind ligands with good physicochemical properties (often termed drug-like). Here, we devise fpocketR , a computational strategy that accurately detects pockets capable of binding drug-like ligands in RNA structures. Remarkably few, roughly 50, of such pockets have ever been visualized. We experimentally confirmed the ligandability of novel pockets detected with fpocketR using a fragment-based approach introduced here, Frag-MaP, that detects ligand-binding sites in cells. Analysis of pockets detected by fpocketR and validated by Frag-MaP reveals dozens of sites able to bind drug-like ligands, supports a model for RNA secondary structural motifs able to bind quality ligands, and creates a broad framework for understanding the RNA ligand-ome.