7dq8

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

spinqualitylabelsall models 7dq8, resolution 2.40Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7dq8 is a 4 chain structure with sequence from Streptomyces sp. and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.4Å Ligands: DSN, DVA, MG, MVA, N2C, NCY, PXZ, QUI, SAR Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed 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. Synergistic binding of actinomycin D and echinomycin to DNA mismatch sites and their combined anti-tumour effects.,Satange R, Chang CC, Li LY, Lin SH, Neidle S, Hou MH Nucleic Acids Res. 2023 May 8;51(8):3540-3555. doi: 10.1093/nar/gkad156. PMID:36919604 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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