Molecular Recognition of the Hybrid-2 Human Telomeric G-Quadruplex by Epiberberine: Insights into Conversion of Telomeric G-Quadruplex Structures

Clement Lin, Guanhui Wu, Kaibo Wang, Buket Onel, Saburo Sakai, Yong Shao, Danzhou Yang

Research output: Contribution to journalArticle

20 Scopus citations


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.

Original languageEnglish (US)
JournalAngewandte Chemie - International Edition
StateAccepted/In press - Jan 1 2018
Externally publishedYes



  • Anticancer drug targets
  • Berberine
  • G-quadruplexes
  • G4-drug complexes
  • Human telomeres
  • NMR spectroscopy

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)

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