Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue Center for Cancer Research, Purdue University, West Lafayette, IN, 47906, USA.
Institute of Biogeochemistry, Japan Agency for Marine-Earth Science and Technology, Yokosuka, Kanagawa, 237-0061, Japan.
Angew Chem Int Ed Engl. 2018 Aug 20;57(34):10888-10893. doi: 10.1002/anie.201804667. Epub 2018 Jul 18.
Human telomeres can form DNA G-quadruplex (G4), an attractive target for anticancer drugs. Human telomeric G4s bear inherent structure polymorphism, challenging for understanding specific recognition by ligands or proteins. Protoberberines are medicinal natural-products known to stabilize telomeric G4s and inhibit telomerase. Here we report epiberberine (EPI) specifically recognizes the hybrid-2 telomeric G4 predominant in physiologically relevant K solution and converts other telomeric G4 forms to hybrid-2, the first such example reported. Our NMR structure in K solution shows EPI binding induces extensive rearrangement of the previously disordered 5'-flanking and loop segments to form an unprecedented four-layer binding pocket specific to the hybrid-2 telomeric G4; EPI recruits the (-1) adenine to form a "quasi-triad" intercalated between the external tetrad and a T:T:A triad, capped by a T:T base pair. Our study provides structural basis for small-molecule drug design targeting the human telomeric G4.
人类端粒可以形成 DNA G-四链体 (G4)，这是一种有吸引力的抗癌药物靶点。人类端粒 G4 具有固有的结构多态性，这使得理解配体或蛋白质的特异性识别具有挑战性。小檗碱是一种已知能稳定端粒 G4 并抑制端粒酶的药用天然产物。在这里，我们报告表小檗碱 (EPI) 特异性识别生理相关 K 溶液中主要存在的杂交-2 端粒 G4，并将其他端粒 G4 形式转化为杂交-2，这是首例此类报道。我们在 K 溶液中的 NMR 结构表明，EPI 结合诱导了以前无规的 5'-侧翼和环段的广泛重排，形成了一个前所未有的四层结合口袋，专门针对杂交-2 端粒 G4；EPI 招募 (-1) 腺嘌呤形成一个“准三联体”，插入外部四联体和 T:T:A 三联体之间，由 T:T 碱基对封顶。我们的研究为针对人类端粒 G4 的小分子药物设计提供了结构基础。
