期刊
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
卷 57, 期 34, 页码 10888-10893出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.201804667
关键词
anticancer drug targets; G4-drug complexes; human telomeres; G-quadruplexes; NMR spectroscopy; berberine
资金
- U.S. National Institutes of Health [R01CA122952, R01CA177585, P30CA023168]
- China National Natural Science Foundation [21675142]
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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