Summary information

PDB id
8jfq
Class
DNA
Method
NMR
Summary
Structure of the major g-quadruplex in the human egfr oncogene promoter adopts a unique folding topology with a distinctive snap-back loop
Reference
Liu Y, Li J, Zhang Y, Wang Y, Chen J, Bian Y, Xia Y, Yang MH, Zheng K, Wang KB, Kong LY (2023): "Structure of the Major G-Quadruplex in the Human EGFR Oncogene Promoter Adopts a Unique Folding Topology with a Distinctive Snap-Back Loop." J.Am.Chem.Soc., 145, 16228-16237. doi: 10.1021/jacs.3c05214.
Abstract
EGFR tyrosine kinase inhibitors have made remarkable success in targeted cancer therapy. However, therapeutic resistance inevitably occurred and EGFR-targeting therapy has been demonstrated to have limited efficacy or utility in glioblastoma, colorectal cancer, and hepatocellular carcinoma. Therefore, there is a high demand for the development of new targets to inhibit EGFR signaling. Herein, we found that the EGFR oncogene proximal promoter sequence forms a unique type of snap-back loop containing G-quadruplex (G4), which can be targeted by small molecules. For the first time, we determined the NMR solution structure of this snap-back EGFR-G4, a three-tetrad-core, parallel-stranded G4 with naturally occurring flanking residues at both the 5'-end and 3'-end. The snap-back loop located at the 3'-end region forms a stable capping structure through two stacked G-triads connected by multiple potential hydrogen bonds. Notably, the flanking residues are consistently absent in reported snap-back G4s, raising the question of whether such structures truly exist under in vivo conditions. The resolved EGFR-G4 structure has eliminated the doubt and showed distinct structural features that distinguish it from the previously reported snap-back G4s, which lack the flanking residues. Furthermore, we found that the snap-back EGFR-G4 structure is highly stable and can form on an elongated DNA template to inhibit DNA polymerase. The unprecedented high-resolution EGFR-G4 structure has thus contributed a promising molecular target for developing alternative EGFR signaling inhibitors in cancer therapeutics. Meanwhile, the two stacked triads may provide an attractive site for specific small-molecule targeting.
G4 notes
3 G-tetrads, 1 G4 helix, 1 G4 stem, 2(-P-P-P), parallel(4+0), UUUU

Base-block schematics in six views

PyMOL session file PDB file View in 3Dmol.js

List of 3 G-tetrads

 1 glyco-bond=---- sugar=---- groove=---- planarity=0.216 type=other  nts=4 GGGG X.DG4,X.DG8,X.DG12,X.DG16
 2 glyco-bond=---- sugar=---- groove=---- planarity=0.228 type=other  nts=4 GGGG X.DG5,X.DG9,X.DG13,X.DG17
 3 glyco-bond=---- sugar=---. groove=---- planarity=0.135 type=planar nts=4 GGGG X.DG6,X.DG24,X.DG14,X.DG18

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 X.DG4,X.DG8,X.DG12,X.DG16
 2  glyco-bond=---- sugar=---- groove=---- WC-->Major nts=4 GGGG X.DG5,X.DG9,X.DG13,X.DG17
 3  glyco-bond=---- sugar=---. groove=---- WC-->Major nts=4 GGGG X.DG6,X.DG24,X.DG14,X.DG18
  step#1  pm(>>,forward)  area=11.71 rise=3.31 twist=29.7
  step#2  pm(>>,forward)  area=14.63 rise=3.36 twist=26.0
  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.DG24
  strand#3 DNA glyco-bond=--- sugar=--- nts=3 GGG X.DG12,X.DG13,X.DG14
  strand#4 DNA glyco-bond=--- sugar=--. nts=3 GGG X.DG16,X.DG17,X.DG18

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2 stacking diagrams 
 1  glyco-bond=---- sugar=---- groove=---- WC-->Major nts=4 GGGG X.DG4,X.DG8,X.DG12,X.DG16
 2  glyco-bond=---- sugar=---- groove=---- WC-->Major nts=4 GGGG X.DG5,X.DG9,X.DG13,X.DG17
  step#1  pm(>>,forward)  area=11.71 rise=3.31 twist=29.7

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 2  glyco-bond=---- sugar=---- groove=---- WC-->Major nts=4 GGGG X.DG5,X.DG9,X.DG13,X.DG17
 3  glyco-bond=---- sugar=---. groove=---- WC-->Major nts=4 GGGG X.DG6,X.DG24,X.DG14,X.DG18
  step#2  pm(>>,forward)  area=14.63 rise=3.36 twist=26.0

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

 1  glyco-bond=---- sugar=---- groove=---- WC-->Major nts=4 GGGG X.DG4,X.DG8,X.DG12,X.DG16
 2  glyco-bond=---- sugar=---- groove=---- WC-->Major nts=4 GGGG X.DG5,X.DG9,X.DG13,X.DG17
  step#1  pm(>>,forward)  area=11.71 rise=3.31 twist=29.7
  strand#1  U DNA glyco-bond=-- sugar=-- nts=2 GG X.DG4,X.DG5
  strand#2  U DNA glyco-bond=-- sugar=-- nts=2 GG X.DG8,X.DG9
  strand#3  U DNA glyco-bond=-- sugar=-- nts=2 GG X.DG12,X.DG13
  strand#4  U DNA glyco-bond=-- sugar=-- nts=2 GG X.DG16,X.DG17
  loop#1 type=propeller strands=[#1,#2] nts=2 GA X.DG6,X.DA7
  loop#2 type=propeller strands=[#2,#3] nts=2 CA X.DC10,X.DA11
  loop#3 type=propeller strands=[#3,#4] nts=2 GC X.DG14,X.DC15

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List of 1 non-stem G4-loop (including the two closing Gs)

 1 type=diagonal  helix=#1 nts=7 GAGGAAG X.DG18,X.DA19,X.DG20,X.DG21,X.DA22,X.DA23,X.DG24