DSSR-enabled G4 identification/annotation: PDB entry 6kxz
Summary information and primary citation
- 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)]<sub>4</sub>, comprising human telomeric DNA sequence TTAGGG, using <sub>1</sub>H and <sub>31</sub>P 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 <sub>31</sub>P 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, UUUU, parallel, 4+0
Cartoon-block schematics in six views (download the tarball)
List of 3 G-tetrads
1 glyco-bond=---- sugar=---- groove=---- planarity=0.803 type=other -- nts=4 GGGG A.DG4,D.DG25,C.DG18,B.DG11 2 glyco-bond=---- sugar=...- groove=---- planarity=0.796 type=other -- nts=4 GGGG A.DG5,D.DG26,C.DG19,B.DG12 3 glyco-bond=---- sugar=---- groove=---- planarity=0.859 type=other -- nts=4 GGGG A.DG6,D.DG27,C.DG20,B.DG13
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-tetrads, inter-molecular, with 1 stem
|
1 glyco-bond=---- sugar=---- groove=---- WC-->Major -- nts=4 GGGG A.DG4,D.DG25,C.DG18,B.DG11 2 glyco-bond=---- sugar=...- groove=---- WC-->Major -- nts=4 GGGG A.DG5,D.DG26,C.DG19,B.DG12 3 glyco-bond=---- sugar=---- groove=---- WC-->Major -- nts=4 GGGG A.DG6,D.DG27,C.DG20,B.DG13 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 D.DG25,D.DG26,D.DG27 strand#3 DNA glyco-bond=--- sugar=-.- nts=3 GGG C.DG18,C.DG19,C.DG20 strand#4 DNA glyco-bond=--- sugar=--- nts=3 GGG B.DG11,B.DG12,B.DG13 |
| 2 stacking diagrams | |
|
1 glyco-bond=---- sugar=---- groove=---- WC-->Major -- nts=4 GGGG A.DG4,D.DG25,C.DG18,B.DG11 |
|
2 glyco-bond=---- sugar=...- groove=---- WC-->Major -- nts=4 GGGG A.DG5,D.DG26,C.DG19,B.DG12 |
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-tetrads, 0 loops, inter-molecular, UUUU, parallel, 4+0
|
1 glyco-bond=---- sugar=---- groove=---- WC-->Major -- nts=4 GGGG A.DG4,D.DG25,C.DG18,B.DG11 2 glyco-bond=---- sugar=...- groove=---- WC-->Major -- nts=4 GGGG A.DG5,D.DG26,C.DG19,B.DG12 3 glyco-bond=---- sugar=---- groove=---- WC-->Major -- nts=4 GGGG A.DG6,D.DG27,C.DG20,B.DG13 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 D.DG25,D.DG26,D.DG27 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 B.DG11,B.DG12,B.DG13 |