Summary information

PDB id
6s15
Class
DNA
Method
X-ray (1.7 Å)
Summary
Pyridine derivative of the natural alkaloid berberine as human telomeric g-quadruplex binder
Reference
Papi F, Bazzicalupi C, Ferraroni M, Ciolli G, Lombardi P, Khan AY, Kumar GS, Gratteri P (2020): "Pyridine Derivative of the Natural Alkaloid Berberine as Human Telomeric G4-DNA Binder: A Solution and Solid-State Study." Acs Med.Chem.Lett., 11, 645-650. doi: 10.1021/acsmedchemlett.9b00516.
Abstract
Telomerase is an enzyme deputed to the maintenance of eukaryotic chromosomes; however, its overexpression is a recognized hallmark of many cancer forms. A viable route for the inhibition of telomerase in malignant cells is the stabilization of G-quadruplex structures (G4) at the 3' overhang of telomeres. Berberine has shown in this regard valuable G4 binding properties together with a significant anticancer activity and telomerase inhibition effects. Here, we focused on a berberine derivative featuring a pyridine containing side group at the 13th position. Such modification actually improves the binding toward telomeric G-quadruplexes and establishes a degree of selectivity in the interaction with different sequences. Moreover, the X-ray crystal structure obtained for the complex formed by the ligand and a bimolecular human telomeric quadruplex affords a better understanding of the 13-berberine derivatives behavior with telomeric G4 and allows to draw useful insights for the future design of derivatives with remarkable anticancer properties.
G4 notes
3 G-tetrads, 1 G4 helix, 1 G4 stem, parallel(4+0), UUUU

Base-block schematics in six views

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List of 3 G-tetrads

 1 glyco-bond=---- sugar=---- groove=---- planarity=0.109 type=planar nts=4 GGGG A.DG3,A.DG9,B.DG15,B.DG21
 2 glyco-bond=---- sugar=---- groove=---- planarity=0.144 type=planar nts=4 GGGG A.DG4,A.DG10,B.DG16,B.DG22
 3 glyco-bond=---- sugar=---- groove=---- planarity=0.306 type=bowl   nts=4 GGGG A.DG5,A.DG11,B.DG17,B.DG23

List of 1 G4-helix

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, inter-molecular, with 1 stem

 1  glyco-bond=---- sugar=---- groove=---- WC-->Major nts=4 GGGG A.DG3,A.DG9,B.DG15,B.DG21
 2  glyco-bond=---- sugar=---- groove=---- WC-->Major nts=4 GGGG A.DG4,A.DG10,B.DG16,B.DG22
 3  glyco-bond=---- sugar=---- groove=---- WC-->Major nts=4 GGGG A.DG5,A.DG11,B.DG17,B.DG23
  step#1  pm(>>,forward)  area=10.28 rise=3.34 twist=29.4
  step#2  pm(>>,forward)  area=12.04 rise=3.42 twist=26.9
  strand#1 DNA glyco-bond=--- sugar=--- nts=3 GGG A.DG3,A.DG4,A.DG5
  strand#2 DNA glyco-bond=--- sugar=--- nts=3 GGG A.DG9,A.DG10,A.DG11
  strand#3 DNA glyco-bond=--- sugar=--- nts=3 GGG B.DG15,B.DG16,B.DG17
  strand#4 DNA glyco-bond=--- sugar=--- nts=3 GGG B.DG21,B.DG22,B.DG23

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2 stacking diagrams 
 1  glyco-bond=---- sugar=---- groove=---- WC-->Major nts=4 GGGG A.DG3,A.DG9,B.DG15,B.DG21
 2  glyco-bond=---- sugar=---- groove=---- WC-->Major nts=4 GGGG A.DG4,A.DG10,B.DG16,B.DG22
  step#1  pm(>>,forward)  area=10.28 rise=3.34 twist=29.4

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 2  glyco-bond=---- sugar=---- groove=---- WC-->Major nts=4 GGGG A.DG4,A.DG10,B.DG16,B.DG22
 3  glyco-bond=---- sugar=---- groove=---- WC-->Major nts=4 GGGG A.DG5,A.DG11,B.DG17,B.DG23
  step#2  pm(>>,forward)  area=12.04 rise=3.42 twist=26.9

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List of 1 G4-stem

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, 2 loops, inter-molecular, UUUU, parallel, parallel(4+0)

 1  glyco-bond=---- sugar=---- groove=---- WC-->Major nts=4 GGGG A.DG3,A.DG9,B.DG15,B.DG21
 2  glyco-bond=---- sugar=---- groove=---- WC-->Major nts=4 GGGG A.DG4,A.DG10,B.DG16,B.DG22
 3  glyco-bond=---- sugar=---- groove=---- WC-->Major nts=4 GGGG A.DG5,A.DG11,B.DG17,B.DG23
  step#1  pm(>>,forward)  area=10.28 rise=3.34 twist=29.4
  step#2  pm(>>,forward)  area=12.04 rise=3.42 twist=26.9
  strand#1  U DNA glyco-bond=--- sugar=--- nts=3 GGG A.DG3,A.DG4,A.DG5
  strand#2  U DNA glyco-bond=--- sugar=--- nts=3 GGG A.DG9,A.DG10,A.DG11
  strand#3  U DNA glyco-bond=--- sugar=--- nts=3 GGG B.DG15,B.DG16,B.DG17
  strand#4  U DNA glyco-bond=--- sugar=--- nts=3 GGG B.DG21,B.DG22,B.DG23
  loop#1 type=propeller strands=[#1,#2] nts=3 TTA A.DT6,A.DT7,A.DA8
  loop#2 type=propeller strands=[#3,#4] nts=3 TTA B.DT18,B.DT19,B.DA20

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