Summary information

PDB id
6kxz
Class
DNA
Method
NMR
Summary
Human parallel stranded 7-mer g-quadruplex complexed with 2 epirubicin (epi) molecules
Reference
Barthwal R, Raje S, Pandav K (2020): "Structural basis for stabilization of human telomeric G-quadruplex [d-(TTAGGGT)] 4 by anticancer drug epirubicin." Bioorg.Med.Chem., 28, 115761. doi: 10.1016/j.bmc.2020.115761.
Abstract
Anthracycline anticancer drugs show multiple strategies of action on gene functioning by regulation of telomerase enzyme by apoptotic factors, e.g. ceramide level, p53 activity, bcl-2 protein levels, besides inhibiting DNA/RNA synthesis and topoisomerase-II action. We report binding of epirubicin with G-quadruplex (G4) DNA, [d-(TTAGGGT)]4, comprising human telomeric DNA sequence TTAGGG, using 1H and 31P NMR spectroscopy. Diffusion ordered spectroscopy, sequence selective changes in chemical shift (~0.33 ppm) and line broadening in DNA signals suggest formation of a well-defined complex. Presence of sequential nuclear Overhauser enhancements at all base quartet steps and absence of large downfield shifts in 31P resonances preclude intercalative mode of interaction. Restrained molecular dynamics simulations using AMBER force field incorporating intermolecular drug to DNA interproton distances, involving ring D protons of epirubicin depict external binding close to T1-T2-A3 and G6pT7 sites. Binding induced thermal stabilization of G4 DNA (~36 °C), obtained from imino protons and differential scanning calorimetry, is likely to come in the way of telomerase association with telomeres. The findings pave the way for drug-designing with modifications at ring D and daunosamine sugar.
G4 notes
3 G-tetrads, 1 G4 helix, 1 G4 stem, parallel(4+0), UUUU

Base-block schematics in six views

PyMOL session file PDB file View in 3Dmol.js

List of 3 G-tetrads

 1 glyco-bond=---- sugar=---- groove=---- planarity=0.803 type=other  nts=4 GGGG A.DG4,B.DG11,C.DG18,D.DG25
 2 glyco-bond=---- sugar=.-.. groove=---- planarity=0.796 type=other  nts=4 GGGG A.DG5,B.DG12,C.DG19,D.DG26
 3 glyco-bond=---- sugar=---- groove=---- planarity=0.859 type=other  nts=4 GGGG A.DG6,B.DG13,C.DG20,D.DG27

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=---- Major-->WC nts=4 GGGG A.DG4,B.DG11,C.DG18,D.DG25
 2  glyco-bond=---- sugar=.-.. groove=---- Major-->WC nts=4 GGGG A.DG5,B.DG12,C.DG19,D.DG26
 3  glyco-bond=---- sugar=---- groove=---- Major-->WC nts=4 GGGG A.DG6,B.DG13,C.DG20,D.DG27
  step#1  pm(>>,forward)  area=12.71 rise=3.93 twist=21.9
  step#2  pm(>>,forward)  area=7.22  rise=4.19 twist=21.7
  strand#1 DNA glyco-bond=--- sugar=-.- nts=3 GGG A.DG4,A.DG5,A.DG6
  strand#2 DNA glyco-bond=--- sugar=--- nts=3 GGG B.DG11,B.DG12,B.DG13
  strand#3 DNA glyco-bond=--- sugar=-.- nts=3 GGG C.DG18,C.DG19,C.DG20
  strand#4 DNA glyco-bond=--- sugar=-.- nts=3 GGG D.DG25,D.DG26,D.DG27

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2 stacking diagrams 
 1  glyco-bond=---- sugar=---- groove=---- Major-->WC nts=4 GGGG A.DG4,B.DG11,C.DG18,D.DG25
 2  glyco-bond=---- sugar=.-.. groove=---- Major-->WC nts=4 GGGG A.DG5,B.DG12,C.DG19,D.DG26
  step#1  pm(>>,forward)  area=12.71 rise=3.93 twist=21.9

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 2  glyco-bond=---- sugar=.-.. groove=---- Major-->WC nts=4 GGGG A.DG5,B.DG12,C.DG19,D.DG26
 3  glyco-bond=---- sugar=---- groove=---- Major-->WC nts=4 GGGG A.DG6,B.DG13,C.DG20,D.DG27
  step#2  pm(>>,forward)  area=7.22  rise=4.19 twist=21.7

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

 1  glyco-bond=---- sugar=---- groove=---- Major-->WC nts=4 GGGG A.DG4,B.DG11,C.DG18,D.DG25
 2  glyco-bond=---- sugar=.-.. groove=---- Major-->WC nts=4 GGGG A.DG5,B.DG12,C.DG19,D.DG26
 3  glyco-bond=---- sugar=---- groove=---- Major-->WC nts=4 GGGG A.DG6,B.DG13,C.DG20,D.DG27
  step#1  pm(>>,forward)  area=12.71 rise=3.93 twist=21.9
  step#2  pm(>>,forward)  area=7.22  rise=4.19 twist=21.7
  strand#1  U DNA glyco-bond=--- sugar=-.- nts=3 GGG A.DG4,A.DG5,A.DG6
  strand#2  U DNA glyco-bond=--- sugar=--- nts=3 GGG B.DG11,B.DG12,B.DG13
  strand#3  U DNA glyco-bond=--- sugar=-.- nts=3 GGG C.DG18,C.DG19,C.DG20
  strand#4  U DNA glyco-bond=--- sugar=-.- nts=3 GGG D.DG25,D.DG26,D.DG27

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