DSSR-enabled G4 identification/annotation: PDB entry 7msv
Summary information and primary citation
- PDB-id
- 7msv
- Class
- DNA
- Method
- NMR
- Summary
- Solution structure of berberine bound to a dgmp fill-in g-quadruplex in the pdgfr-b promoter
- Reference
- Wang KB, Dickerhoff J, Yang D (2021): "Solution Structure of Ternary Complex of Berberine Bound to a dGMP-Fill-In Vacancy G-Quadruplex Formed in the PDGFR-beta Promoter." J.Am.Chem.Soc., 143, 16549-16555. doi: 10.1021/jacs.1c06200.
- Abstract
- The G-quadruplexes (G4s) formed in the <i>PDGFR-β</i> gene promoter are transcriptional modulators and amenable to small-molecule targeting. Berberine (BER), a clinically important natural isoquinoline alkaloid, has gained increasing attention due to its potential as anticancer drug. We previously showed that the <i>PDGFR-β</i> gene promoter forms a unique vacancy G4 (vG4) that can be filled in and stabilized by guanine metabolites, such as dGMP. Herein, we report the high-resolution NMR structure of a ternary complex of berberine bound to the dGMP-fill-in PDGFR-β vG4 in potassium solution. This is the first small-molecule complex structure of a fill-in vG4. This ternary complex has a 2:1:1 binding stoichiometry with a berberine molecule bound at each the 5'- and 3'-end of the 5'-dGMP-fill-in PDGFR-β vG4. Each berberine recruits the adjacent adenine residue from the 5'- or 3'-flanking sequence to form a "quasi-triad plane" that covers the external G-tetrad of the fill-in vG4, respectively. Significantly, berberine covers and stabilizes the fill-in dGMP. The binding of berberine involves both π-stacking and electrostatic interactions, and the fill-in dGMP is covered and well-protected by berberine. The NMR structure can guide rational design of berberine analogues that target the PDGFR-β vG4 or dGMP-fill-in vG4. Moreover, our structure provides a molecular basis for designing small-molecule guanine conjugates to target vG4s.
- 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=0.415 type=other N+ nts=4 GGgG X.DG3,X.DG7,X.DGP101,X.DG14 2 glyco-bond=---- sugar=---- groove=---- planarity=0.152 type=planar O+ nts=4 GGGG X.DG4,X.DG8,X.DG11,X.DG15 3 glyco-bond=---- sugar=---- groove=---- planarity=0.146 type=planar 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
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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=13.67 rise=3.34 twist=28.0 step#2 pm(>>,forward) area=12.95 rise=3.41 twist=28.5 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=12.95 rise=3.41 twist=28.5 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 |