6CCW

Hybrid-2 form Human Telomeric G Quadruplex in Complex with Epiberberine

Summary for 6CCW

• Entry DOI: 10.2210/pdb6ccw/pdb
• NMR Information: BMRB: 30402
• Descriptor: DNA (26-MER), Epiberberine (2 entities in total)
• Functional Keywords: g-quadruplex, complex, telomere, dna
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 8536.63

Authors

Lin, C.,Yang, D.Z. (deposition date: 2018-02-07, release date: 2018-06-20, Last modification date: 2024-05-15)

Primary citation

Lin, C.,Wu, G.,Wang, K.,Onel, B.,Sakai, S.,Shao, Y.,Yang, D.
Molecular Recognition of the Hybrid-2 Human Telomeric G-Quadruplex by Epiberberine: Insights into Conversion of Telomeric G-Quadruplex Structures.
Angew. Chem. Int. Ed. Engl., 57:10888-10893, 2018

PubMed 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.

PubMed: 29888501
DOI: 10.1002/anie.201804667

Experimental method

SOLUTION NMR