Summary information

PDB id
3cdm
Class
DNA
Method
X-ray (2.1 Å)
Summary
Structural adaptation and conservation in quadruplex-drug recognition
Reference
Parkinson GN, Cuenca F, Neidle S (2008): "Topology conservation and loop flexibility in quadruplex-drug recognition: crystal structures of inter- and intramolecular telomeric DNA quadruplex-drug complexes." J.Mol.Biol., 381, 1145-1156. doi: 10.1016/j.jmb.2008.06.022.
Abstract
Knowledge of the biologically relevant topology is critical for the design of drugs targeting quadruplex nucleic acids. We report here crystal structures of a G-quadruplex-selective ligand complexed with two human telomeric DNA quadruplexes. The intramolecular quadruplex sequence d[TAGGG(TTAGGG)(3)] and the bimolecular quadruplex sequence d(TAGGGTTAGGGT) were co-crystallized with a tetra-substituted naphthalene diimide quadruplex-binding ligand. The structures were solved and refined to 2.10- and 2.20-A resolution, respectively, revealing that the quadruplex topology in both structures is unchanged by the addition of the ligands, retaining a parallel-stranded arrangement with external double-chain-reversal propeller loops. The parallel topology results in accessible external 5' and 3' planar G-tetrad surfaces for ligand stacking. This also enables significant ligand-induced conformational changes in several TTA propeller loops to take place such that the loops themselves are able to accommodate bound drug molecules without affecting the parallel quadruplex topology, by stacking on the external TTA connecting loop nucleotides. Ligands are bound into the external TTA loop nucleotides and stack onto G-tetrad surfaces. These crystal structures provide a framework for further ligand development of the naphthalene diimide series to enhance selectivity and affinity.
G4 notes
6 G-tetrads, 2 G4 helices, 2 G4 stems, 3(-P-P-P), parallel(4+0), UUUU

Base-block schematics in six views

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List of 6 G-tetrads

 1 glyco-bond=---- sugar=---- groove=---- planarity=0.074 type=planar nts=4 GGGG A.DG3,A.DG9,A.DG15,A.DG21
 2 glyco-bond=---- sugar=---- groove=---- planarity=0.128 type=planar nts=4 GGGG A.DG4,A.DG10,A.DG16,A.DG22
 3 glyco-bond=---- sugar=---- groove=---- planarity=0.272 type=bowl   nts=4 GGGG A.DG5,A.DG11,A.DG17,A.DG23
 4 glyco-bond=---- sugar=---- groove=---- planarity=0.103 type=planar nts=4 GGGG B.DG3,B.DG9,B.DG15,B.DG21
 5 glyco-bond=---- sugar=---- groove=---- planarity=0.179 type=other  nts=4 GGGG B.DG4,B.DG10,B.DG16,B.DG22
 6 glyco-bond=---- sugar=---- groove=---- planarity=0.293 type=bowl   nts=4 GGGG B.DG5,B.DG11,B.DG17,B.DG23

List of 2 G4-helices

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=---- sugar=---- groove=---- WC-->Major nts=4 GGGG A.DG3,A.DG9,A.DG15,A.DG21
 2  glyco-bond=---- sugar=---- groove=---- WC-->Major nts=4 GGGG A.DG4,A.DG10,A.DG16,A.DG22
 3  glyco-bond=---- sugar=---- groove=---- WC-->Major nts=4 GGGG A.DG5,A.DG11,A.DG17,A.DG23
  step#1  pm(>>,forward)  area=9.22  rise=3.38 twist=30.1
  step#2  pm(>>,forward)  area=13.01 rise=3.38 twist=26.0
  strand#1 DNA glyco-bond=--- sugar=--- nts=3 GGG A.DG3,A.DG4,A.DG5
  strand#2 DNA glyco-bond=--- sugar=--- nts=3 GGG A.DG9,A.DG10,A.DG11
  strand#3 DNA glyco-bond=--- sugar=--- nts=3 GGG A.DG15,A.DG16,A.DG17
  strand#4 DNA glyco-bond=--- sugar=--- nts=3 GGG A.DG21,A.DG22,A.DG23

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2 stacking diagrams 
 1  glyco-bond=---- sugar=---- groove=---- WC-->Major nts=4 GGGG A.DG3,A.DG9,A.DG15,A.DG21
 2  glyco-bond=---- sugar=---- groove=---- WC-->Major nts=4 GGGG A.DG4,A.DG10,A.DG16,A.DG22
  step#1  pm(>>,forward)  area=9.22  rise=3.38 twist=30.1

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 2  glyco-bond=---- sugar=---- groove=---- WC-->Major nts=4 GGGG A.DG4,A.DG10,A.DG16,A.DG22
 3  glyco-bond=---- sugar=---- groove=---- WC-->Major nts=4 GGGG A.DG5,A.DG11,A.DG17,A.DG23
  step#2  pm(>>,forward)  area=13.01 rise=3.38 twist=26.0

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Helix#2, 3 G-tetrad layers, INTRA-molecular, with 1 stem

 1  glyco-bond=---- sugar=---- groove=---- WC-->Major nts=4 GGGG B.DG3,B.DG9,B.DG15,B.DG21
 2  glyco-bond=---- sugar=---- groove=---- WC-->Major nts=4 GGGG B.DG4,B.DG10,B.DG16,B.DG22
 3  glyco-bond=---- sugar=---- groove=---- WC-->Major nts=4 GGGG B.DG5,B.DG11,B.DG17,B.DG23
  step#1  pm(>>,forward)  area=11.22 rise=3.38 twist=28.4
  step#2  pm(>>,forward)  area=12.93 rise=3.41 twist=27.0
  strand#1 DNA glyco-bond=--- sugar=--- nts=3 GGG B.DG3,B.DG4,B.DG5
  strand#2 DNA glyco-bond=--- sugar=--- nts=3 GGG B.DG9,B.DG10,B.DG11
  strand#3 DNA glyco-bond=--- sugar=--- nts=3 GGG B.DG15,B.DG16,B.DG17
  strand#4 DNA glyco-bond=--- sugar=--- nts=3 GGG B.DG21,B.DG22,B.DG23

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2 stacking diagrams 
 1  glyco-bond=---- sugar=---- groove=---- WC-->Major nts=4 GGGG B.DG3,B.DG9,B.DG15,B.DG21
 2  glyco-bond=---- sugar=---- groove=---- WC-->Major nts=4 GGGG B.DG4,B.DG10,B.DG16,B.DG22
  step#1  pm(>>,forward)  area=11.22 rise=3.38 twist=28.4

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 2  glyco-bond=---- sugar=---- groove=---- WC-->Major nts=4 GGGG B.DG4,B.DG10,B.DG16,B.DG22
 3  glyco-bond=---- sugar=---- groove=---- WC-->Major nts=4 GGGG B.DG5,B.DG11,B.DG17,B.DG23
  step#2  pm(>>,forward)  area=12.93 rise=3.41 twist=27.0

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List of 2 G4-stems

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=---- sugar=---- groove=---- WC-->Major nts=4 GGGG A.DG3,A.DG9,A.DG15,A.DG21
 2  glyco-bond=---- sugar=---- groove=---- WC-->Major nts=4 GGGG A.DG4,A.DG10,A.DG16,A.DG22
 3  glyco-bond=---- sugar=---- groove=---- WC-->Major nts=4 GGGG A.DG5,A.DG11,A.DG17,A.DG23
  step#1  pm(>>,forward)  area=9.22  rise=3.38 twist=30.1
  step#2  pm(>>,forward)  area=13.01 rise=3.38 twist=26.0
  strand#1  U DNA glyco-bond=--- sugar=--- nts=3 GGG A.DG3,A.DG4,A.DG5
  strand#2  U DNA glyco-bond=--- sugar=--- nts=3 GGG A.DG9,A.DG10,A.DG11
  strand#3  U DNA glyco-bond=--- sugar=--- nts=3 GGG A.DG15,A.DG16,A.DG17
  strand#4  U DNA glyco-bond=--- sugar=--- nts=3 GGG A.DG21,A.DG22,A.DG23
  loop#1 type=propeller strands=[#1,#2] nts=3 TTA A.DT6,A.DT7,A.DA8
  loop#2 type=propeller strands=[#2,#3] nts=3 TTA A.DT12,A.DT13,A.DA14
  loop#3 type=propeller strands=[#3,#4] nts=3 TTA A.DT18,A.DT19,A.DA20

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Stem#2, 3 G-tetrad layers, 3 loops, INTRA-molecular, UUUU, parallel, 3(-P-P-P), parallel(4+0)

 1  glyco-bond=---- sugar=---- groove=---- WC-->Major nts=4 GGGG B.DG3,B.DG9,B.DG15,B.DG21
 2  glyco-bond=---- sugar=---- groove=---- WC-->Major nts=4 GGGG B.DG4,B.DG10,B.DG16,B.DG22
 3  glyco-bond=---- sugar=---- groove=---- WC-->Major nts=4 GGGG B.DG5,B.DG11,B.DG17,B.DG23
  step#1  pm(>>,forward)  area=11.22 rise=3.38 twist=28.4
  step#2  pm(>>,forward)  area=12.93 rise=3.41 twist=27.0
  strand#1  U DNA glyco-bond=--- sugar=--- nts=3 GGG B.DG3,B.DG4,B.DG5
  strand#2  U DNA glyco-bond=--- sugar=--- nts=3 GGG B.DG9,B.DG10,B.DG11
  strand#3  U DNA glyco-bond=--- sugar=--- nts=3 GGG B.DG15,B.DG16,B.DG17
  strand#4  U DNA glyco-bond=--- sugar=--- nts=3 GGG B.DG21,B.DG22,B.DG23
  loop#1 type=propeller strands=[#1,#2] nts=3 TTA B.DT6,B.DT7,B.DA8
  loop#2 type=propeller strands=[#2,#3] nts=3 TTA B.DT12,B.DT13,B.DA14
  loop#3 type=propeller strands=[#3,#4] nts=3 TTA B.DT18,B.DT19,B.DA20

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