DSSR-enabled G4 identification/annotation: PDB entry 6v0l
Summary information and primary citation
- PDB-id
- 6v0l
- Class
- DNA
- Method
- NMR
- Summary
- Pdgfr-b promoter forms a g-vacancy quadruplex that can be complemented by dgmp: molecular structure and recognition of guanine derivatives and metabolites
- Reference
- Wang KB, Dickerhoff J, Wu G, Yang D (2020): "PDGFR-beta Promoter Forms a Vacancy G-Quadruplex that Can Be Filled in by dGMP: Solution Structure and Molecular Recognition of Guanine Metabolites and Drugs." J.Am.Chem.Soc., 142, 5204-5211. doi: 10.1021/jacs.9b12770.
- Abstract
- Aberrant expression of PDGFR-β is associated with a number of diseases. The G-quadruplexes (G4s) formed in PDGFR-β gene promoter are transcriptional modulators and amenable to small molecule targeting. The major G4 formed in the PDGFR-β gene promoter was previously shown to have a broken G-strand. Herein, we report that the PDGFR-β gene promoter sequence forms a vacancy G-quadruplex (vG4) which can be filled in and stabilized by physiologically relevant guanine metabolites, such as dGMP, GMP, and cGMP, as well as guanine-derivative drugs. We determined the NMR structure of the dGMP-fill-in PDGFR-β vG4 in K<sub>+</sub> solution. This is the first structure of a guanine-metabolite-fill-in vG4 based on a human gene promoter sequence. Our structure and systematic analysis elucidate the contributions of Hoogsten hydrogen bonds, sugar, and phosphate moieties to the specific G-vacancy fill-in. Intriguingly, an equilibrium of 3'- and 5'-end vG4s is present in the PDGFR-β promoter sequence, and dGMP favors the 5'-end fill-in. Guanine metabolites and drugs were tested and showed a conserved selectivity for the 5'-vacancy, except for cGMP. cGMP binds both the 3'- and 5'-end vG4s and forms two fill-in G4s with similar population. Significantly, guanine metabolites are involved in many physiological and pathological processes in human cells; thus, our results provide a structural basis to understand their potential regulatory functions by interaction with promoter vG4s. Moreover, the NMR structure can guide rational design of ligands that target the PDGFR-β vG4.
- G4 notes
- 3 G-tetrads, 1 G4 helix, 1 G4 stem, UUUU, parallel, 4+0, 2(-P-P-P)
Cartoon-block schematics in six views (download the tarball)
List of 3 G-tetrads
1 glyco-bond=---- sugar=---- groove=---- planarity=0.480 type=other N+ nts=4 GGgG X.DG3,X.DG7,X.DGP101,X.DG14 2 glyco-bond=---- sugar=---- groove=---- planarity=0.296 type=bowl-2 O+ nts=4 GGGG X.DG4,X.DG8,X.DG11,X.DG15 3 glyco-bond=---- sugar=---- groove=---- planarity=0.344 type=bowl O+ nts=4 GGGG X.DG5,X.DG9,X.DG12,X.DG16
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 N+ nts=4 GGgG X.DG3,X.DG7,X.DGP101,X.DG14 2 glyco-bond=---- sugar=---- groove=---- WC-->Major O+ nts=4 GGGG X.DG4,X.DG8,X.DG11,X.DG15 3 glyco-bond=---- sugar=---- groove=---- WC-->Major O+ nts=4 GGGG X.DG5,X.DG9,X.DG12,X.DG16 step#1 pm(>>,forward) area=16.08 rise=3.47 twist=21.5 step#2 pm(>>,forward) area=13.01 rise=3.52 twist=26.4 strand#1 DNA glyco-bond=--- sugar=--- nts=3 GGG X.DG3,X.DG4,X.DG5 strand#2 DNA glyco-bond=--- sugar=--- nts=3 GGG X.DG7,X.DG8,X.DG9 strand#3 DNA glyco-bond=--- sugar=--- nts=3 gGG X.DGP101,X.DG11,X.DG12 strand#4 DNA glyco-bond=--- sugar=--- nts=3 GGG X.DG14,X.DG15,X.DG16 |
| 2 stacking diagrams | |
|
1 glyco-bond=---- sugar=---- groove=---- WC-->Major N+ nts=4 GGgG X.DG3,X.DG7,X.DGP101,X.DG14 |
|
2 glyco-bond=---- sugar=---- groove=---- WC-->Major O+ nts=4 GGGG X.DG4,X.DG8,X.DG11,X.DG15 |
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-tetrads, 3 loops, INTRA-molecular, UUUU, parallel, 4+0, 2(-P-P-P)
|
1 glyco-bond=---- sugar=---- groove=---- WC-->Major O+ nts=4 GGGG X.DG4,X.DG8,X.DG11,X.DG15 2 glyco-bond=---- sugar=---- groove=---- WC-->Major O+ nts=4 GGGG X.DG5,X.DG9,X.DG12,X.DG16 step#1 pm(>>,forward) area=13.01 rise=3.52 twist=26.4 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.DG11,X.DG12 strand#4 U DNA glyco-bond=-- sugar=-- nts=2 GG X.DG15,X.DG16 loop#1 type=propeller strands=[#1,#2] nts=2 AG X.DA6,X.DG7 loop#2 type=propeller strands=[#2,#3] nts=1 C X.DC10 loop#3 type=propeller strands=[#3,#4] nts=2 CG X.DC13,X.DG14 |