Summary information

PDB id
7n7d
Class
DNA
Method
NMR
Summary
Solution structure of the myc promoter g-quadruplex in complex with berberine: conformer a
Reference
Dickerhoff J, Brundridge N, McLuckey SA, Yang D (2021): "Berberine Molecular Recognition of the Parallel MYC G-Quadruplex in Solution." J.Med.Chem., 64, 16205-16212. doi: 10.1021/acs.jmedchem.1c01508.
Abstract
The medicinal natural product berberine is one of the most actively studied and pursued G-quadruplex (G4)-ligands. The major G-quadruplex formed in the promoter region of the MYC oncogene (MycG4) is an attractive drug target and a prominent example and model structure for parallel G-quadruplexes. G4-targeted berberine derivatives have been actively developed; however, the analogue design was based on a previous crystal structure in which berberine binds as a dimer to a parallel G-quadruplex. Herein, we show that in solution, the binding mode and stoichiometry of berberine are substantially different from the crystal structure: berberine binds as a monomer to MycG4 using a base-recruitment mechanism with a reversed orientation in that the positively charged convex side is actually positioned above the tetrad center. Our structure provides a physiologically relevant basis for the future structure-based rational design of G4-targeted berberine derivatives, and this study demonstrates that it is crucial to validate the ligand-DNA interactions.
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

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List of 3 G-tetrads

 1 glyco-bond=---- sugar=---- groove=---- planarity=0.197 type=other  nts=4 GGGG A.DG7,A.DG11,A.DG16,A.DG20
 2 glyco-bond=---- sugar=---- groove=---- planarity=0.157 type=planar nts=4 GGGG A.DG8,A.DG12,A.DG17,A.DG21
 3 glyco-bond=---- sugar=---- groove=---- planarity=0.161 type=other  nts=4 GGGG A.DG9,A.DG13,A.DG18,A.DG22

List of 1 G4-helix

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.DG7,A.DG11,A.DG16,A.DG20
 2  glyco-bond=---- sugar=---- groove=---- WC-->Major nts=4 GGGG A.DG8,A.DG12,A.DG17,A.DG21
 3  glyco-bond=---- sugar=---- groove=---- WC-->Major nts=4 GGGG A.DG9,A.DG13,A.DG18,A.DG22
  step#1  pm(>>,forward)  area=8.37  rise=3.39 twist=33.2
  step#2  pm(>>,forward)  area=16.78 rise=3.40 twist=23.8
  strand#1 DNA glyco-bond=--- sugar=--- nts=3 GGG A.DG7,A.DG8,A.DG9
  strand#2 DNA glyco-bond=--- sugar=--- nts=3 GGG A.DG11,A.DG12,A.DG13
  strand#3 DNA glyco-bond=--- sugar=--- nts=3 GGG A.DG16,A.DG17,A.DG18
  strand#4 DNA glyco-bond=--- sugar=--- nts=3 GGG A.DG20,A.DG21,A.DG22

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2 stacking diagrams
 1  glyco-bond=---- sugar=---- groove=---- WC-->Major nts=4 GGGG A.DG7,A.DG11,A.DG16,A.DG20
2 glyco-bond=---- sugar=---- groove=---- WC-->Major nts=4 GGGG A.DG8,A.DG12,A.DG17,A.DG21
step#1 pm(>>,forward) area=8.37 rise=3.39 twist=33.2

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 2  glyco-bond=---- sugar=---- groove=---- WC-->Major nts=4 GGGG A.DG8,A.DG12,A.DG17,A.DG21
3 glyco-bond=---- sugar=---- groove=---- WC-->Major nts=4 GGGG A.DG9,A.DG13,A.DG18,A.DG22
step#2 pm(>>,forward) area=16.78 rise=3.40 twist=23.8

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List of 1 G4-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.

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.DG7,A.DG11,A.DG16,A.DG20
 2  glyco-bond=---- sugar=---- groove=---- WC-->Major nts=4 GGGG A.DG8,A.DG12,A.DG17,A.DG21
 3  glyco-bond=---- sugar=---- groove=---- WC-->Major nts=4 GGGG A.DG9,A.DG13,A.DG18,A.DG22
  step#1  pm(>>,forward)  area=8.37  rise=3.39 twist=33.2
  step#2  pm(>>,forward)  area=16.78 rise=3.40 twist=23.8
  strand#1  U DNA glyco-bond=--- sugar=--- nts=3 GGG A.DG7,A.DG8,A.DG9
  strand#2  U DNA glyco-bond=--- sugar=--- nts=3 GGG A.DG11,A.DG12,A.DG13
  strand#3  U DNA glyco-bond=--- sugar=--- nts=3 GGG A.DG16,A.DG17,A.DG18
  strand#4  U DNA glyco-bond=--- sugar=--- 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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