Summary information [schematics · tetrads · helices · stems · costacks · homepage]

PDB-id
4da3
Class
DNA
Method
X-ray (2.4 Å)
Summary
Crystal structure of an intramolecular human telomeric DNA G-quadruplex 21-mer bound by the naphthalene diimide compound mm41
Reference
Micco, M., Collie, G.W., Dale, A.G., Ohnmacht, S.A., Pazitna, I., Gunaratnam, M., Reszka, A.P., Neidle, S.: (2013) "Structure-based design and evaluation of naphthalene diimide g-quadruplex ligands as telomere targeting agents in pancreatic cancer cells." J.Med.Chem., 56, 2959-2974.
Abstract
Tetra-substituted naphthalene diimide (ND) derivatives with positively charged termini are potent stabilizers of human telomeric and gene promoter DNA quadruplexes and inhibit the growth of human cancer cells in vitro and in vivo. The present study reports the enhancement of the pharmacological properties of earlier ND compounds using structure-based design. Crystal structures of three complexes with human telomeric intramolecular quadruplexes demonstrate that two of the four strongly basic N-methyl-piperazine groups can be replaced by less basic morpholine groups with no loss of intermolecular interactions in the grooves of the quadruplex. The new compounds retain high affinity to human telomeric quadruplex DNA but are 10-fold more potent against the MIA PaCa-2 pancreatic cancer cell line, with IC50 values of ~10 nM. The lead compound induces cellular senescence but does not inhibit telomerase activity at the nanomolar dosage levels required for inhibition of cellular proliferation. Gene array qPCR analysis of MIA PaCa-2 cells treated with the lead compound revealed significant dose-dependent modulation of a distinct subset of genes, including strong induction of DNA damage responsive genes CDKN1A, DDIT3, GADD45A/G, and PPM1D, and repression of genes involved in telomere maintenance, including hPOT1 and PARP1.
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]

PyMOL session file PDB file View in 3Dmol.js

List of 3 G-tetrads [summary · schematics · helices · stems · costacks · homepage]

 1 glyco-bond=---- groove=---- planarity=0.201 type=other  nts=4 GGGG A.DG1,A.DG7,A.DG13,A.DG19
 2 glyco-bond=---- groove=---- planarity=0.095 type=planar nts=4 GGGG A.DG2,A.DG8,A.DG14,A.DG20
 3 glyco-bond=---- groove=---- planarity=0.337 type=bowl   nts=4 GGGG A.DG3,A.DG9,A.DG15,A.DG21

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.DG1,A.DG7,A.DG13,A.DG19
 2  glyco-bond=---- groove=---- WC-->Major nts=4 GGGG A.DG2,A.DG8,A.DG14,A.DG20
 3  glyco-bond=---- groove=---- WC-->Major nts=4 GGGG A.DG3,A.DG9,A.DG15,A.DG21
  step#1  pm(>>,forward)  area=8.98  rise=3.31 twist=33.5
  step#2  pm(>>,forward)  area=14.14 rise=3.61 twist=23.7
  strand#1 DNA glyco-bond=--- nts=3 GGG A.DG1,A.DG2,A.DG3
  strand#2 DNA glyco-bond=--- nts=3 GGG A.DG7,A.DG8,A.DG9
  strand#3 DNA glyco-bond=--- nts=3 GGG A.DG13,A.DG14,A.DG15
  strand#4 DNA glyco-bond=--- nts=3 GGG A.DG19,A.DG20,A.DG21

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2 stacking diagrams
 1  glyco-bond=---- groove=---- WC-->Major nts=4 GGGG A.DG1,A.DG7,A.DG13,A.DG19
2 glyco-bond=---- groove=---- WC-->Major nts=4 GGGG A.DG2,A.DG8,A.DG14,A.DG20
step#1 pm(>>,forward) area=8.98 rise=3.31 twist=33.5

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 2  glyco-bond=---- groove=---- WC-->Major nts=4 GGGG A.DG2,A.DG8,A.DG14,A.DG20
3 glyco-bond=---- groove=---- WC-->Major nts=4 GGGG A.DG3,A.DG9,A.DG15,A.DG21
step#2 pm(>>,forward) area=14.14 rise=3.61 twist=23.7

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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.DG1,A.DG7,A.DG13,A.DG19
 2  glyco-bond=---- groove=---- WC-->Major nts=4 GGGG A.DG2,A.DG8,A.DG14,A.DG20
 3  glyco-bond=---- groove=---- WC-->Major nts=4 GGGG A.DG3,A.DG9,A.DG15,A.DG21
  step#1  pm(>>,forward)  area=8.98  rise=3.31 twist=33.5
  step#2  pm(>>,forward)  area=14.14 rise=3.61 twist=23.7
  strand#1  U DNA glyco-bond=--- nts=3 GGG A.DG1,A.DG2,A.DG3
  strand#2  U DNA glyco-bond=--- nts=3 GGG A.DG7,A.DG8,A.DG9
  strand#3  U DNA glyco-bond=--- nts=3 GGG A.DG13,A.DG14,A.DG15
  strand#4  U DNA glyco-bond=--- nts=3 GGG A.DG19,A.DG20,A.DG21
  loop#1 type=propeller strands=[#1,#2] nts=3 TTA A.DT4,A.DT5,A.DA6
  loop#2 type=propeller strands=[#2,#3] nts=3 TTA A.DT10,A.DT11,A.DA12
  loop#3 type=propeller strands=[#3,#4] nts=3 TTA A.DT16,A.DT17,A.DA18

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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)