Molecular insights into de novo small-molecule recognition by an intron RNA structure.

ABSTRACT: Despite the promise of vastly expanding the druggable genome, rational design of RNA-targeting ligands remains challenging as it requires the rapid identification of hits and visualization of the resulting cocomplexes for guiding optimization. Here, we leveraged high-throughput screening, medicinal chemistry, and structural biology to identify a de novo splicing inhibitor against a large and highly folded fungal group I intron. High-resolution cryoEM structures of the intron in different liganded states not only reveal molecular interactions that rationalize experimental structure-activity relationship but also shed light on a unique strategy whereby RNA-associated metal ions and RNA conformation exhibit exceptional plasticity in response to small-molecule binding. This study reveals gener

SUBMITTER: Liu T 

PROVIDER: S-EPMC12088405 | biostudies-literature | 2025 May

REPOSITORIES: biostudies-literature