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

PDB-id
5w77
Class
DNA-inhibitor
Method
NMR
Summary
Complex of DNA and compounds
Reference
Calabrese, D.R., Chen, X., Leon, E.C., Gaikwad, S.M., Phyo, Z., Hewitt, W.M., Alden, S., Hilimire, T.A., He, F., Michalowski, A.M., Simmons, J.K., Saunders, L.B., Zhang, S., Connors, D., Walters, K.J., Mock, B.A., Schneekloth Jr., J.S.: (2018) "Chemical and structural studies provide a mechanistic basis for recognition of the MYC G-quadruplex." Nat Commun, 9, 4229-4229.
Abstract
G-quadruplexes (G4s) are noncanonical DNA structures that frequently occur in the promoter regions of oncogenes, such as MYC, and regulate gene expression. Although G4s are attractive therapeutic targets, ligands capable of discriminating between different G4 structures are rare. Here, we describe DC-34, a small molecule that potently downregulates MYC transcription in cancer cells by a G4-dependent mechanism. Inhibition by DC-34 is significantly greater for MYC than other G4-driven genes. We use chemical, biophysical, biological, and structural studies to demonstrate a molecular rationale for the recognition of the MYC G4. We solve the structure of the MYC G4 in complex with DC-34 by NMR spectroscopy and illustrate specific contacts responsible for affinity and selectivity. Modification of DC-34 reveals features required for G4 affinity, biological activity, and validates the derived NMR structure. This work advances the design of quadruplex-interacting small molecules to control gene expression in therapeutic areas such as cancer.
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=0.062 type=planar nts=4 GGGG A.DG7,A.DG11,A.DG16,A.DG20
 2 glyco-bond=---- groove=---- planarity=0.047 type=planar nts=4 GGGG A.DG8,A.DG12,A.DG17,A.DG21
 3 glyco-bond=---- groove=---- planarity=0.136 type=planar nts=4 GGGG A.DG9,A.DG13,A.DG18,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.DG7,A.DG11,A.DG16,A.DG20
 2  glyco-bond=---- groove=---- WC-->Major nts=4 GGGG A.DG8,A.DG12,A.DG17,A.DG21
 3  glyco-bond=---- groove=---- WC-->Major nts=4 GGGG A.DG9,A.DG13,A.DG18,A.DG22
  step#1  pm(>>,forward)  area=13.01 rise=3.21 twist=26.0
  step#2  pm(>>,forward)  area=12.50 rise=3.53 twist=28.3
  strand#1 DNA glyco-bond=--- nts=3 GGG A.DG7,A.DG8,A.DG9
  strand#2 DNA glyco-bond=--- nts=3 GGG A.DG11,A.DG12,A.DG13
  strand#3 DNA glyco-bond=--- nts=3 GGG A.DG16,A.DG17,A.DG18
  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.DG7,A.DG11,A.DG16,A.DG20
2 glyco-bond=---- groove=---- WC-->Major nts=4 GGGG A.DG8,A.DG12,A.DG17,A.DG21
step#1 pm(>>,forward) area=13.01 rise=3.21 twist=26.0

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 2  glyco-bond=---- groove=---- WC-->Major nts=4 GGGG A.DG8,A.DG12,A.DG17,A.DG21
3 glyco-bond=---- groove=---- WC-->Major nts=4 GGGG A.DG9,A.DG13,A.DG18,A.DG22
step#2 pm(>>,forward) area=12.50 rise=3.53 twist=28.3

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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.DG7,A.DG11,A.DG16,A.DG20
 2  glyco-bond=---- groove=---- WC-->Major nts=4 GGGG A.DG8,A.DG12,A.DG17,A.DG21
 3  glyco-bond=---- groove=---- WC-->Major nts=4 GGGG A.DG9,A.DG13,A.DG18,A.DG22
  step#1  pm(>>,forward)  area=13.01 rise=3.21 twist=26.0
  step#2  pm(>>,forward)  area=12.50 rise=3.53 twist=28.3
  strand#1  U DNA glyco-bond=--- nts=3 GGG A.DG7,A.DG8,A.DG9
  strand#2  U DNA glyco-bond=--- nts=3 GGG A.DG11,A.DG12,A.DG13
  strand#3  U DNA glyco-bond=--- nts=3 GGG A.DG16,A.DG17,A.DG18
  strand#4  U DNA glyco-bond=--- nts=3 GGG A.DG20,A.DG21,A.DG22
  loop#1 type=propeller strands=[#1,#2] nts=1 T A.DT10
  loop#2 type=propeller strands=[#2,#3] nts=2 TA A.DT14,A.DA15
  loop#3 type=propeller strands=[#3,#4] nts=1 T A.DT19

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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)