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

• 成果类型: Article
• 署名作者: Liu, Tianshuo; Xu, Ling; Chung, Kevin; Sisto, Luke J.; Hwang, Jimin; Zhang, Chengxin; Van Zandt, Michael C.; Pyle, Anna Marie
• 署名单位: Yale University; Howard Hughes Medical Institute; Yale University; Yale University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-13352
• DOI: 10.1073/pnas.2502425122
• 发表日期: 2025-05-13
• 关键词: group-i intron; cryo-em; crystal-structure; 2-metal-ion mechanism; tetrahymena; tertiary; ribozyme; inhibition; refinement; DISCOVERY

摘要

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 general principles that govern RNA-ligand recognition, the interplay between chemical bonding specificity, and dynamic responses within an RNA target.