DSSR-derived G-quadruplex features in PDB entry 3t5e
Citation: before a paper dedicated to the DSSR-G4 module comes out, please cite the 2015 DSSR paper published in Nucleic Acids Research.
- X-ray (2.1 Å)
- Crystal structure of an intramolecular human telomeric DNA G-quadruplex bound by the naphthalene diimide bmsg-sh-4
- Collie, G.W., Promontorio, R., Hampel, S.M., Micco, M., Neidle, S., Parkinson, G.N.: (2012) "Structural basis for telomeric g-quadruplex targeting by naphthalene diimide ligands." J.Am.Chem.Soc., 134, 2723-2731.
- The folding of the single-stranded 3' end of the human telomere into G-quadruplex arrangements inhibits the overhang from hybridizing with the RNA template of telomerase and halts telomere maintenance in cancer cells. The ability to thermally stabilize human telomeric DNA as a four-stranded G-quadruplex structure by developing selective small molecule compounds is a therapeutic path to regulating telomerase activity and thereby selectively inhibit cancer cell growth. The development of compounds with the necessary selectivity and affinity to target parallel-stranded G-quadruplex structures has proved particularly challenging to date, relying heavily upon limited structural data. We report here on a structure-based approach to the design of quadruplex-binding ligands to enhance affinity and selectivity for human telomeric DNA. Crystal structures have been determined of complexes between a 22-mer intramolecular human telomeric quadruplex and two potent tetra-substituted naphthalene diimide compounds, functionalized with positively charged N-methyl-piperazine side-chains. These compounds promote parallel-stranded quadruplex topology, binding exclusively to the 3' surface of each quadruplex. There are significant differences between the complexes in terms of ligand mobility and in the interactions with quadruplex grooves. One of the two ligands is markedly less mobile in the crystal complex and is more quadruplex-stabilizing, forming multiple electrostatic/hydrogen bond contacts with quadruplex phosphate groups. The data presented here provides a structural rationale for the biophysical (effects on quadruplex thermal stabilization) and biological data (inhibition of proliferation in cancer cell lines and evidence of in vivo antitumor activity) on compounds in this series and, thus, for the concept of telomere targeting with DNA quadruplex-binding small molecules.
- G4 notes
- 3 G-tetrads, 1 G4 helix, 1 G4 stem · 3(-P-P-P), parallel(4+0), UUUU
1 glyco-bond=---- groove=---- planarity=0.049 type=planar nts=4 GGGG A.DG2,A.DG8,A.DG14,A.DG20 2 glyco-bond=---- groove=---- planarity=0.148 type=planar nts=4 GGGG A.DG3,A.DG9,A.DG15,A.DG21 3 glyco-bond=---- groove=---- planarity=0.274 type=bowl nts=4 GGGG A.DG4,A.DG10,A.DG16,A.DG22
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
In DSSR, a G4-stem is defined as a G4-helix with backbone connectivity. Bulges are also allowed along each of the four strands.