DSSR-enabled G4 identification/annotation: PDB entry 8ebo
Summary information and primary citation
- PDB-id
- 8ebo
- Class
- DNA
- Method
- X-ray (1.98 Å)
- Summary
- Homopurine parallel g-quadruplex from human chromosome 7 stabilized by k+ ions
- Reference
- Ye M, Chen EV, Pfeil SH, Martin KN, Atrafi T, Yun S, Martinez Z, Yatsunyk LA (2022): "Homopurine guanine-rich sequences in complex with N-methyl mesoporphyrin IX form parallel G-quadruplex dimers and display a unique symmetry tetrad." Bioorg.Med.Chem., 77, 117112. doi: 10.1016/j.bmc.2022.117112.
- Abstract
- DNA can fold into G-quadruplexes (GQs), non-canonical secondary structures formed by π-π stacking of G-tetrads. GQs are important in many biological processes, which makes them promising therapeutic targets. We identified a 42-nucleotide long, purine-only G-rich sequence from human genome, which contains eight G-stretches connected by A and AAAA loops. We divided this sequence into five unique segments, four guanine stretches each, named GA1-5. In order to investigate the role of adenines in GQ structure formation, we performed biophysical and X-ray crystallographic studies of GA1-5 and their complexes with a highly selective GQ ligand, N-methyl mesoporphyrin IX (NMM). Our data indicate that all variants form parallel GQs whose stability depends on the number of flexible AAAA loops. GA1-3 bind NMM with 1:1 stoichiometry. The K<sub>a</sub> for GA1 and GA3 is modest, ∼0.3 μM <sub>-</sub><sub>1</sub>, and that for GA2 is significantly higher, ∼1.2 μM <sub>-</sub><sub>1</sub>. NMM stabilizes GA1-3 by 14.6, 13.1, and 7.0 ℃, respectively, at 2 equivalents. We determined X-ray crystal structures of GA1-NMM (1.98 Å resolution) and GA3-NMM (2.01 Å). The structures confirm the parallel topology of GQs with all adenines forming loops and display NMM binding at the 3' G-tetrad. Both complexes dimerize through the 5' interface. We observe two novel structural features: 1) a 'symmetry tetrad' at the dimer interface, which is formed by two guanines from each GQ monomer and 2) a NMM dimer in GA1-NMM. Our structural work confirms great flexibility of adenines as structural elements in GQ formation and contributes greatly to our understanding of the structural diversity of GQs and their modes of interaction with small molecule ligands.
- 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)
List of 3 G-tetrads
1 glyco-bond=---- sugar=---- groove=---- planarity=0.126 type=planar O+ nts=4 GGGG A.DG3,A.DG7,A.DG11,A.DG19 2 glyco-bond=---- sugar=---- groove=---- planarity=0.132 type=planar O+ nts=4 GGGG A.DG4,A.DG8,A.DG12,A.DG20 3 glyco-bond=---- sugar=---- groove=---- planarity=0.320 type=bowl O+ nts=4 GGGG A.DG5,A.DG9,A.DG13,A.DG21
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 A.DG3,A.DG7,A.DG11,A.DG19 2 glyco-bond=---- sugar=---- groove=---- WC-->Major O+ nts=4 GGGG A.DG4,A.DG8,A.DG12,A.DG20 3 glyco-bond=---- sugar=---- groove=---- WC-->Major O+ nts=4 GGGG A.DG5,A.DG9,A.DG13,A.DG21 step#1 pm(>>,forward) area=9.52 rise=3.34 twist=32.4 step#2 pm(>>,forward) area=13.13 rise=3.46 twist=27.2 strand#1 DNA glyco-bond=--- sugar=--- nts=3 GGG A.DG3,A.DG4,A.DG5 strand#2 DNA glyco-bond=--- sugar=--- nts=3 GGG A.DG7,A.DG8,A.DG9 strand#3 DNA glyco-bond=--- sugar=--- nts=3 GGG A.DG11,A.DG12,A.DG13 strand#4 DNA glyco-bond=--- sugar=--- nts=3 GGG A.DG19,A.DG20,A.DG21 |
| 2 stacking diagrams | |
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1 glyco-bond=---- sugar=---- groove=---- WC-->Major O+ nts=4 GGGG A.DG3,A.DG7,A.DG11,A.DG19 |
|
2 glyco-bond=---- sugar=---- groove=---- WC-->Major O+ nts=4 GGGG A.DG4,A.DG8,A.DG12,A.DG20 |
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 A.DG3,A.DG7,A.DG11,A.DG19 2 glyco-bond=---- sugar=---- groove=---- WC-->Major O+ nts=4 GGGG A.DG4,A.DG8,A.DG12,A.DG20 3 glyco-bond=---- sugar=---- groove=---- WC-->Major O+ nts=4 GGGG A.DG5,A.DG9,A.DG13,A.DG21 step#1 pm(>>,forward) area=9.52 rise=3.34 twist=32.4 step#2 pm(>>,forward) area=13.13 rise=3.46 twist=27.2 strand#1 U DNA glyco-bond=--- sugar=--- nts=3 GGG A.DG3,A.DG4,A.DG5 strand#2 U DNA glyco-bond=--- sugar=--- nts=3 GGG A.DG7,A.DG8,A.DG9 strand#3 U DNA glyco-bond=--- sugar=--- nts=3 GGG A.DG11,A.DG12,A.DG13 strand#4 U DNA glyco-bond=--- sugar=--- nts=3 GGG A.DG19,A.DG20,A.DG21 loop#1 type=propeller strands=[#1,#2] nts=1 A A.DA6 loop#2 type=propeller strands=[#2,#3] nts=1 A A.DA10 loop#3 type=propeller strands=[#3,#4] nts=5 AAAAG A.DA14,A.DA15,A.DA16,A.DA17,A.DG18 |