7DQ0

Crystal structure of actinomycin D-echinomycin-d(ACGTGCT/AGCTCGT) complex

7DQ0 の概要

• エントリーDOI: 10.2210/pdb7dq0/pdb
• 関連するBIRD辞書のPRD_ID: PRD_000001 PRD_000491
• 分子名称: DNA (5'-D(P*AP*GP*CP*TP*CP*GP*T)-3'), Actinomycin D, Echinomycin, ... (8 entities in total)
• 機能のキーワード: drug-dna complex, dna mismatch, dna unwinding, dna deformation, dna, antibiotic-dna complex, antibiotic/dna
• 由来する生物種: Streptomyces sp.; 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 6907.27

構造登録者

Satange, R.B.,Hou, M.H. (登録日: 2020-12-22, 公開日: 2021-12-29, 最終更新日: 2024-07-10)

主引用文献

Satange, R.,Chang, C.C.,Li, L.Y.,Lin, S.H.,Neidle, S.,Hou, M.H.
Synergistic binding of actinomycin D and echinomycin to DNA mismatch sites and their combined anti-tumour effects.
Nucleic Acids Res., 2023

PubMed Abstract: Combination cancer chemotherapy is one of the most useful treatment methods to achieve a synergistic effect and reduce the toxicity of dosing with a single drug. Here, we use a combination of two well-established anticancer DNA intercalators, actinomycin D (ActD) and echinomycin (Echi), to screen their binding capabilities with DNA duplexes containing different mismatches embedded within Watson-Crick base-pairs. We have found that combining ActD and Echi preferentially stabilised thymine-related T:T mismatches. The enhanced stability of the DNA duplex-drug complexes is mainly due to the cooperative binding of the two drugs to the mismatch duplex, with many stacking interactions between the two different drug molecules. Since the repair of thymine-related mismatches is less efficient in mismatch repair (MMR)-deficient cancer cells, we have also demonstrated that the combination of ActD and Echi exhibits enhanced synergistic effects against MMR-deficient HCT116 cells and synergy is maintained in a MMR-related MLH1 gene knockdown in SW620 cells. We further accessed the clinical potential of the two-drug combination approach with a xenograft mouse model of a colorectal MMR-deficient cancer, which has resulted in a significant synergistic anti-tumour effect. The current study provides a novel approach for the development of combination chemotherapy for the treatment of cancers related to DNA-mismatches.

PubMed: 36919604
DOI: 10.1093/nar/gkad156

実験手法

X-RAY DIFFRACTION (2 Å)