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PDB-id
3t5e
Class
DNA
Method
X-ray (2.1 Å)
Summary
Crystal structure of an intramolecular human telomeric DNA G-quadruplex bound by the naphthalene diimide bmsg-sh-4
Reference
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.
Abstract
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

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=---- 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

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=---- groove=---- WC-->Major nts=4 GGGG A.DG2,A.DG8,A.DG14,A.DG20
 2  glyco-bond=---- groove=---- WC-->Major nts=4 GGGG A.DG3,A.DG9,A.DG15,A.DG21
 3  glyco-bond=---- groove=---- WC-->Major nts=4 GGGG A.DG4,A.DG10,A.DG16,A.DG22
  step#1  pm(>>,forward)  area=10.99 rise=3.43 twist=29.0
  step#2  pm(>>,forward)  area=11.56 rise=3.50 twist=28.4
  strand#1 DNA glyco-bond=--- nts=3 GGG A.DG2,A.DG3,A.DG4
  strand#2 DNA glyco-bond=--- nts=3 GGG A.DG8,A.DG9,A.DG10
  strand#3 DNA glyco-bond=--- nts=3 GGG A.DG14,A.DG15,A.DG16
  strand#4 DNA glyco-bond=--- nts=3 GGG A.DG20,A.DG21,A.DG22

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2 stacking diagrams
 1  glyco-bond=---- groove=---- WC-->Major nts=4 GGGG A.DG2,A.DG8,A.DG14,A.DG20
2 glyco-bond=---- groove=---- WC-->Major nts=4 GGGG A.DG3,A.DG9,A.DG15,A.DG21
step#1 pm(>>,forward) area=10.99 rise=3.43 twist=29.0

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 2  glyco-bond=---- groove=---- WC-->Major nts=4 GGGG A.DG3,A.DG9,A.DG15,A.DG21
3 glyco-bond=---- groove=---- WC-->Major nts=4 GGGG A.DG4,A.DG10,A.DG16,A.DG22
step#2 pm(>>,forward) area=11.56 rise=3.50 twist=28.4

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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, UUUU, parallel, 3(-P-P-P), parallel(4+0)

 1  glyco-bond=---- groove=---- WC-->Major nts=4 GGGG A.DG2,A.DG8,A.DG14,A.DG20
 2  glyco-bond=---- groove=---- WC-->Major nts=4 GGGG A.DG3,A.DG9,A.DG15,A.DG21
 3  glyco-bond=---- groove=---- WC-->Major nts=4 GGGG A.DG4,A.DG10,A.DG16,A.DG22
  step#1  pm(>>,forward)  area=10.99 rise=3.43 twist=29.0
  step#2  pm(>>,forward)  area=11.56 rise=3.50 twist=28.4
  strand#1  U DNA glyco-bond=--- nts=3 GGG A.DG2,A.DG3,A.DG4
  strand#2  U DNA glyco-bond=--- nts=3 GGG A.DG8,A.DG9,A.DG10
  strand#3  U DNA glyco-bond=--- nts=3 GGG A.DG14,A.DG15,A.DG16
  strand#4  U DNA glyco-bond=--- nts=3 GGG A.DG20,A.DG21,A.DG22
  loop#1 type=propeller strands=[#1,#2] nts=3 TTA A.DT5,A.DT6,A.DA7
  loop#2 type=propeller strands=[#2,#3] nts=3 TTA A.DT11,A.DT12,A.DA13
  loop#3 type=propeller strands=[#3,#4] nts=3 TTA A.DT17,A.DT18,A.DA19

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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)