Molecular Recognition of the Hybrid‐2 Human Telomeric G‐Quadruplex by Epiberberine: Insights into Conversion of Telomeric G‐Quadruplex Structures |
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| Authors: | Dr Clement Lin Guanhui Wu Dr Kaibo Wang Dr Buket Onel Dr Saburo Sakai Prof Yong Shao Prof Danzhou Yang |
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| Institution: | 1. Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue Center for Cancer Research, Purdue University, West Lafayette, IN, USA;2. Institute of Biogeochemistry, Japan Agency for Marine-Earth Science and Technology, Yokosuka, Kanagawa, Japan;3. College of Chemistry and Life Sciences, Zhejiang Normal University, Jinhua, China |
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| Abstract: | 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. |
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| Keywords: | anticancer drug targets G4-drug complexes human telomeres G-quadruplexes NMR spectroscopy berberine |
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