The medicinal natural product berberine is one of the most actively studied and pursued G-quadruplex (G4)-ligands. The major G-quadruplex formed in the promoter region of the MYC oncogene (MycG4) is an attractive drug target and a prominent example and model structure for parallel G-quadruplexes. G4-targeted berberine derivatives have been actively developed; however, the analogue design was based on a previous crystal structure in which berberine binds as a dimer to a parallel G-quadruplex. Herein, we show that in solution, the binding mode and stoichiometry of berberine are substantially different from the crystal structure: berberine binds as a monomer to MycG4 using a base-recruitment mechanism with a reversed orientation in that the positively charged convex side is actually positioned above the tetrad center. Our structure provides a physiologically relevant basis for the future structure-based rational design of G4-targeted berberine derivatives, and this study demonstrates that it is crucial to validate the ligand–DNA interactions.

中文翻译：

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溶液中平行 MYC G-四联体的小檗碱分子识别

药用天然产物小檗碱是最活跃研究和追求的 G-四联体 (G4)-配体之一。在 MYC 致癌基因 (MycG4) 的启动子区域中形成的主要 G-四链体是一个有吸引力的药物靶标，也是平行 G-四链体的突出示例和模型结构。积极开发G4靶向小檗碱衍生物；然而，模拟设计是基于先前的晶体结构，其中小檗碱作为二聚体与平行的 G-四链体结合。在此，我们表明在溶液中，小檗碱的结合模式和化学计量与晶体结构有很大不同：小檗碱作为单体与 MycG4 结合，使用具有反向取向的碱基募集机制，因为带正电的凸面实际上位于在四分体中心之上。