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PDB-id
6ccw
Class
DNA
Method
NMR
Summary
Hybrid-2 form human telomeric g quadruplex in complex with epiberberine
Reference
Lin, C., Wu, G., Wang, K., Onel, B., Sakai, S., Shao, Y., Yang, D.: (2018) "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.
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.
G4 notes
3 G-tetrads, 1 G4 helix, 1 G4 stem · 3(-Lw-Ln-P), hybrid-2(3+1), UDUU

Base-block schematics in six views [summary · tetrads · helices · stems · costacks · homepage]

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List of 3 G-tetrads [summary · schematics · helices · stems · costacks · homepage]

 1 glyco-bond=s-ss groove=wn-- planarity=0.262 type=other  nts=4 GGGG A.DG4,A.DG12,A.DG16,A.DG22
 2 glyco-bond=-s-- groove=wn-- planarity=0.153 type=planar nts=4 GGGG A.DG5,A.DG11,A.DG17,A.DG23
 3 glyco-bond=-s-- groove=wn-- planarity=0.129 type=planar nts=4 GGGG A.DG6,A.DG10,A.DG18,A.DG24

List of 1 G4-helix [summary · schematics · tetrads · stems · costacks · homepage]

In DSSR, a G4-helix is defined by stacking interactions of G-tetrads, regardless of backbone connectivity, and may contain more than one G4-stem.

Helix#1, 3 G-tetrad layers, INTRA-molecular, with 1 stem

 1  glyco-bond=s-ss groove=wn-- Major-->WC nts=4 GGGG A.DG4,A.DG12,A.DG16,A.DG22
 2  glyco-bond=-s-- groove=wn-- WC-->Major nts=4 GGGG A.DG5,A.DG11,A.DG17,A.DG23
 3  glyco-bond=-s-- groove=wn-- WC-->Major nts=4 GGGG A.DG6,A.DG10,A.DG18,A.DG24
  step#1  mm(<>,outward)  area=14.70 rise=3.84 twist=17.5
  step#2  pm(>>,forward)  area=14.17 rise=3.66 twist=27.6
  strand#1 DNA glyco-bond=s-- nts=3 GGG A.DG4,A.DG5,A.DG6
  strand#2 DNA glyco-bond=-ss nts=3 GGG A.DG12,A.DG11,A.DG10
  strand#3 DNA glyco-bond=s-- nts=3 GGG A.DG16,A.DG17,A.DG18
  strand#4 DNA glyco-bond=s-- nts=3 GGG A.DG22,A.DG23,A.DG24

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2 stacking diagrams
 1  glyco-bond=s-ss groove=wn-- Major-->WC nts=4 GGGG A.DG4,A.DG12,A.DG16,A.DG22
2 glyco-bond=-s-- groove=wn-- WC-->Major nts=4 GGGG A.DG5,A.DG11,A.DG17,A.DG23
step#1 mm(<>,outward) area=14.70 rise=3.84 twist=17.5

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 2  glyco-bond=-s-- groove=wn-- WC-->Major nts=4 GGGG A.DG5,A.DG11,A.DG17,A.DG23
3 glyco-bond=-s-- groove=wn-- WC-->Major nts=4 GGGG A.DG6,A.DG10,A.DG18,A.DG24
step#2 pm(>>,forward) area=14.17 rise=3.66 twist=27.6

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List of 1 G4-stem [summary · schematics · tetrads · helices · costacks · homepage]

In DSSR, a G4-stem is defined as a G4-helix with backbone connectivity. Bulges are also allowed along each of the four strands.

Stem#1, 3 G-tetrad layers, 3 loops, INTRA-molecular, UDUU, anti-parallel, 3(-Lw-Ln-P), hybrid-2(3+1)

 1  glyco-bond=s-ss groove=wn-- Major-->WC nts=4 GGGG A.DG4,A.DG12,A.DG16,A.DG22
 2  glyco-bond=-s-- groove=wn-- WC-->Major nts=4 GGGG A.DG5,A.DG11,A.DG17,A.DG23
 3  glyco-bond=-s-- groove=wn-- WC-->Major nts=4 GGGG A.DG6,A.DG10,A.DG18,A.DG24
  step#1  mm(<>,outward)  area=14.70 rise=3.84 twist=17.5
  step#2  pm(>>,forward)  area=14.17 rise=3.66 twist=27.6
  strand#1  U DNA glyco-bond=s-- nts=3 GGG A.DG4,A.DG5,A.DG6
  strand#2  D DNA glyco-bond=-ss nts=3 GGG A.DG12,A.DG11,A.DG10
  strand#3  U DNA glyco-bond=s-- nts=3 GGG A.DG16,A.DG17,A.DG18
  strand#4  U DNA glyco-bond=s-- nts=3 GGG A.DG22,A.DG23,A.DG24
  loop#1 type=lateral   strands=[#1,#2] nts=3 TTA A.DT7,A.DT8,A.DA9
  loop#2 type=lateral   strands=[#2,#3] nts=3 TTA A.DT13,A.DT14,A.DA15
  loop#3 type=propeller strands=[#3,#4] nts=3 TTA A.DT19,A.DT20,A.DA21

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List of 0 G4 coaxial stacks [summary · schematics · tetrads · helices · stems · homepage]

List of 0 non-stem G4-loops (including the two closing Gs)