Ligand- binding pockets in RNA and where to find them

• 成果类型: Article
• 署名作者: Veenbaas, Seth D.; Koehn, Jordan T.; Irving, Patrick S.; Lama, Nicole N.; Weeks, Kevin M.
• 署名单位: University of North Carolina; University of North Carolina Chapel Hill
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8489
• DOI: 10.1073/pnas.2422346122
• 发表日期: 2025-04-29
• 关键词: crystal-structure; structural basis; DISCOVERY; shape; aptamer; STATES

摘要

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 ligandbinding 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 ligandbinding 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.