DSSR-enabled G4 identification/annotation: PDB entry 9va3
Summary information and primary citation
- PDB-id
- 9va3
- Class
- DNA
- Method
- NMR
- Summary
- Solution NMR structures of htert DNA g-quadruplexes (g4s) in complex with small molecule zbh-01
- Reference
- Li Y, Ji D, Jia Y, Liang Y, Wei E, Gao C, Li Y, Zeng C, Wang L, Wang C, Guo Z, Zhang Y, Zhou MM, Wu D, Zeng L (2026): "Dual targeting of topoisomerase I and DNA G-quadruplexes enhances senescence and chemosensitivity in colorectal cancer." Commun Biol, 9. doi: 10.1038/s42003-026-09801-w.
- Abstract
- Colorectal cancer (CRC) remains a therapeutic challenge due to chemoresistance that limits conventional treatment efficacy. We developed ZBH-01, a camptothecin derivative engineered to target both topoisomerase I (TOP1) and DNA G-quadruplexes (G4s). Unlike irinotecan (CPT-11), which requires metabolic activation, ZBH-01 directly stabilizes TOP1-DNA covalent complexes and preferentially binds the hTERT promoter G4, a regulator of telomere maintenance and oncogenic transcription. Structural studies reveal that the crescent-shaped scaffold of ZBH-01 π-π stacks onto the external G-tetrad of the hTERT G4, displacing SP1/MYC transcription factors and suppressing hTERT expression. Functionally, ZBH-01 demonstrated improved efficacy in chemoresistant models, exhibiting 14-fold and 7-fold greater efficacy than CPT-11 and SN-38 respectively in cisplatin-resistant cells, and outperforming CPT-11 by 61-fold and SN-38 by 2.4-fold in 5-FU-resistant models. By concurrently disrupting DNA repair through TOP1-trapping and transcriptional adaptation via G4-stabilization, ZBH-01 induced DNA damage, telomere shortening, and cellular senescence. These findings establish TOP1/G4 dual-targeting as a potential therapeutic strategy to enhance CRC chemosensitivity, presenting a new framework for combining DNA damage induction with transcription modulation.
- 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=0.292 type=other O+ nts=4 GGGG A.DG4,A.DG8,A.DG14,A.DG18 2 glyco-bond=---- sugar=-.-. groove=---- planarity=0.231 type=bowl-2 O+ nts=4 GGGG A.DG5,A.DG9,A.DG15,A.DG19 3 glyco-bond=---- sugar=.--- groove=---- planarity=0.237 type=other O+ nts=4 GGGG A.DG6,A.DG10,A.DG16,A.DG20
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.DG4,A.DG8,A.DG14,A.DG18 2 glyco-bond=---- sugar=-.-. groove=---- WC-->Major O+ nts=4 GGGG A.DG5,A.DG9,A.DG15,A.DG19 3 glyco-bond=---- sugar=.--- groove=---- WC-->Major O+ nts=4 GGGG A.DG6,A.DG10,A.DG16,A.DG20 step#1 pm(>>,forward) area=17.87 rise=3.22 twist=26.0 step#2 pm(>>,forward) area=14.24 rise=3.21 twist=27.0 strand#1 DNA glyco-bond=--- sugar=.-. nts=3 GGG A.DG4,A.DG5,A.DG6 strand#2 DNA glyco-bond=--- sugar=-.- nts=3 GGG A.DG8,A.DG9,A.DG10 strand#3 DNA glyco-bond=--- sugar=--- nts=3 GGG A.DG14,A.DG15,A.DG16 strand#4 DNA glyco-bond=--- sugar=-.- nts=3 GGG A.DG18,A.DG19,A.DG20 |
| 2 stacking diagrams | |
|
1 glyco-bond=---- sugar=.--- groove=---- WC-->Major O+ nts=4 GGGG A.DG4,A.DG8,A.DG14,A.DG18 |
|
2 glyco-bond=---- sugar=-.-. groove=---- WC-->Major O+ nts=4 GGGG A.DG5,A.DG9,A.DG15,A.DG19 |
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.DG4,A.DG8,A.DG14,A.DG18 2 glyco-bond=---- sugar=-.-. groove=---- WC-->Major O+ nts=4 GGGG A.DG5,A.DG9,A.DG15,A.DG19 3 glyco-bond=---- sugar=.--- groove=---- WC-->Major O+ nts=4 GGGG A.DG6,A.DG10,A.DG16,A.DG20 step#1 pm(>>,forward) area=17.87 rise=3.22 twist=26.0 step#2 pm(>>,forward) area=14.24 rise=3.21 twist=27.0 strand#1 U DNA glyco-bond=--- sugar=.-. nts=3 GGG A.DG4,A.DG5,A.DG6 strand#2 U DNA glyco-bond=--- sugar=-.- nts=3 GGG A.DG8,A.DG9,A.DG10 strand#3 U DNA glyco-bond=--- sugar=--- nts=3 GGG A.DG14,A.DG15,A.DG16 strand#4 U DNA glyco-bond=--- sugar=-.- nts=3 GGG A.DG18,A.DG19,A.DG20 loop#1 type=propeller strands=[#1,#2] nts=1 A A.DA7 loop#2 type=propeller strands=[#2,#3] nts=3 TCT A.DT11,A.DC12,A.DT13 loop#3 type=propeller strands=[#3,#4] nts=1 A A.DA17 |