8WQ7

Crystal structure of d(CGTATACG)2 with a four-carbon linker containing diacridine compound

Summary for 8WQ7

• Entry DOI: 10.2210/pdb8wq7/pdb
• Descriptor: DNA (5'-D(P*CP*GP*TP*AP*TP*AP*CP*G)-3'), MANGANESE (II) ION, N,N'-di(acridin-9-yl)butane-1,4-diamine, ... (4 entities in total)
• Functional Keywords: drug-dna complex, bis-intercalator, acridine, dna
• Biological source: synthetic construct
• Total number of polymer chains: 2
• Total formula weight: 5405.66

Authors

Huang, S.C.,Satange, R.B.,Hou, M.H. (deposition date: 2023-10-11, release date: 2024-08-07, Last modification date: 2024-09-11)

Primary citation

Huang, S.C.,Chen, C.W.,Satange, R.,Hsieh, C.C.,Chang, C.C.,Wang, S.C.,Peng, C.L.,Chen, T.L.,Chiang, M.H.,Horng, Y.C.,Hou, M.H.
Targeting DNA junction sites by bis-intercalators induces topological changes with potent antitumor effects.
Nucleic Acids Res., 52:9303-9316, 2024

PubMed 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.

PubMed: 39036959
DOI: 10.1093/nar/gkae643

Experimental method

X-RAY DIFFRACTION (1.58 Å)