Summary information and primary citation
- PDB-id
-
8w76;
DSSR-derived features in text and
JSON formats
- Class
- DNA
- Method
- X-ray (2.71 Å)
- Summary
- Crystal structure of d(cgtatacg)2 duplex
- Reference
-
Huang SC, Chen CW, Satange R, Hsieh CC, Chang CC, Wang
SC, Peng CL, Chen TL, Chiang MH, Horng YC, Hou MH (2024):
"Targeting
DNA junction sites by bis-intercalators induces
topological changes with potent antitumor effects."
Nucleic Acids Res., 52,
9303-9316. doi: 10.1093/nar/gkae643.
- Abstract
- Targeting inter-duplex junctions in catenated DNA with
bidirectional bis-intercalators is a potential strategy for
enhancing anticancer effects. In this study, we used
d(CGTATACG)2, which forms a tetraplex base-pair junction
that resembles the DNA-DNA contact structure, as a model
target for two alkyl-linked diaminoacridine
bis-intercalators, DA4 and DA5. Cross-linking of the
junction site by the bis-intercalators induced substantial
structural changes in the DNA, transforming it from a
B-form helical end-to-end junction to an over-wounded
side-by-side inter-duplex conformation with A-DNA
characteristics and curvature. These structural
perturbations facilitated the angled intercalation of DA4
and DA5 with propeller geometry into two adjacent duplexes.
The addition of a single carbon to the DA5 linker caused a
bend that aligned its chromophores with CpG sites, enabling
continuous stacking and specific water-mediated
interactions at the inter-duplex contacts. Furthermore, we
have shown that the different topological changes induced
by DA4 and DA5 lead to the inhibition of topoisomerase 2
activities, which may account for their antitumor effects.
Thus, this study lays the foundations for bis-intercalators
targeting biologically relevant DNA-DNA contact structures
for anticancer drug development.
