Summary information and primary citation

PDB-id
7x8o
Class
DNA
Method
NMR
Summary
NMR solution structure of the 2:1 coptisine-kras-g4 complex
Reference
Wang KB, Liu Y, Li J, Xiao C, Wang Y, Gu W, Li Y, Xia YZ, Yan T, Yang MH, Kong LY (2022): "Structural insight into the bulge-containing KRAS oncogene promoter G-quadruplex bound to berberine and coptisine." Nat Commun, 13, 6016. doi: 10.1038/s41467-022-33761-4.
Abstract
KRAS is one of the most highly mutated oncoproteins, which is overexpressed in various human cancers and implicated in poor survival. The G-quadruplex formed in KRAS oncogene promoter (KRAS-G4) is a transcriptional modulator and amenable to small molecule targeting. However, no available KRAS-G4-ligand complex structure has yet been determined, which seriously hinders the structure-based rational design of KRAS-G4 targeting drugs. In this study, we report the NMR solution structures of a bulge-containing KRAS-G4 bound to berberine and coptisine, respectively. The determined complex structure shows a 2:1 binding stoichiometry with each compound recruiting the adjacent flacking adenine residue to form a "quasi-triad plane" that stacks over the two external G-tetrads. The binding involves both π-stacking and electrostatic interactions. Moreover, berberine and coptisine significantly lowered the KRAS mRNA levels in cancer cells. Our study thus provides molecular details of ligand interactions with KRAS-G4 and is beneficial for the design of specific KRAS-G4-interactive drugs.
G4 notes
3 G-tetrads, 1 G4 helix, 1 G4 stem, UUUU, parallel, 4+0, 3(-P-P-P)

Cartoon-block schematics in six views (download the tarball)

PyMOL session file

Download PDB file

View in 3Dmol.js

List of 3 G-tetrads

 1 glyco-bond=---- sugar=---- groove=---- planarity=0.101 type=planar O+ nts=4 GGGG X.DG4,X.DG8,X.DG13,X.DG20
 2 glyco-bond=---- sugar=-.-- groove=---- planarity=0.238 type=other  O+ nts=4 GGGG X.DG5,X.DG9,X.DG14,X.DG21
 3 glyco-bond=---- sugar=---- groove=---- planarity=0.301 type=bowl   O+ nts=4 GGGG X.DG6,X.DG11,X.DG15,X.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-tetrads, INTRA-molecular, with 1 stem
 1  glyco-bond=---- sugar=---- groove=---- WC-->Major O+ nts=4 GGGG X.DG4,X.DG8,X.DG13,X.DG20
 2  glyco-bond=---- sugar=-.-- groove=---- WC-->Major O+ nts=4 GGGG X.DG5,X.DG9,X.DG14,X.DG21
 3  glyco-bond=---- sugar=---- groove=---- WC-->Major O+ nts=4 GGGG X.DG6,X.DG11,X.DG15,X.DG22
  step#1  pm(>>,forward)  area=13.42 rise=3.44 twist=24.1
  step#2  pm(>>,forward)  area=11.34 rise=3.44 twist=28.6
  strand#1 DNA glyco-bond=--- sugar=--- nts=3 GGG X.DG4,X.DG5,X.DG6
  strand#2 DNA glyco-bond=--- sugar=-.- nts=3 GGG X.DG8,X.DG9,X.DG11
  strand#3 DNA glyco-bond=--- sugar=--- nts=3 GGG X.DG13,X.DG14,X.DG15
  strand#4 DNA glyco-bond=--- sugar=--- nts=3 GGG X.DG20,X.DG21,X.DG22

Download PDB file
Interactive view in 3Dmol.js
2 stacking diagrams 
 1  glyco-bond=---- sugar=---- groove=---- WC-->Major O+ nts=4 GGGG X.DG4,X.DG8,X.DG13,X.DG20
 2  glyco-bond=---- sugar=-.-- groove=---- WC-->Major O+ nts=4 GGGG X.DG5,X.DG9,X.DG14,X.DG21
  step#1  pm(>>,forward)  area=13.42 rise=3.44 twist=24.1

Download PDB file
Interactive view in 3Dmol.js

 
 2  glyco-bond=---- sugar=-.-- groove=---- WC-->Major O+ nts=4 GGGG X.DG5,X.DG9,X.DG14,X.DG21
 3  glyco-bond=---- sugar=---- groove=---- WC-->Major O+ nts=4 GGGG X.DG6,X.DG11,X.DG15,X.DG22
  step#2  pm(>>,forward)  area=11.34 rise=3.44 twist=28.6

Download PDB file
Interactive view in 3Dmol.js

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-tetrads, 3 loops, INTRA-molecular, UUUU, parallel, 4+0, 3(-P-P-P)
 1  glyco-bond=---- sugar=---- groove=---- WC-->Major O+ nts=4 GGGG X.DG4,X.DG8,X.DG13,X.DG20
 2  glyco-bond=---- sugar=-.-- groove=---- WC-->Major O+ nts=4 GGGG X.DG5,X.DG9,X.DG14,X.DG21
 3  glyco-bond=---- sugar=---- groove=---- WC-->Major O+ nts=4 GGGG X.DG6,X.DG11,X.DG15,X.DG22
  step#1  pm(>>,forward)  area=13.42 rise=3.44 twist=24.1
  step#2  pm(>>,forward)  area=11.34 rise=3.44 twist=28.6
  strand#1  U DNA glyco-bond=--- sugar=--- nts=3 GGG X.DG4,X.DG5,X.DG6
  strand#2* U DNA glyco-bond=--- sugar=-.- nts=3 GGG X.DG8,X.DG9,X.DG11 bulged-nts=1 T X.DT10
  strand#3  U DNA glyco-bond=--- sugar=--- nts=3 GGG X.DG13,X.DG14,X.DG15
  strand#4  U DNA glyco-bond=--- sugar=--- nts=3 GGG X.DG20,X.DG21,X.DG22
  loop#1 type=propeller strands=[#1,#2] nts=1 C X.DC7
  loop#2 type=propeller strands=[#2,#3] nts=1 T X.DT12
  loop#3 type=propeller strands=[#3,#4] nts=4 AATA X.DA16,X.DA17,X.DT18,X.DA19

Download PDB file
Interactive view in 3Dmol.js