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|標題:||Cooperative recognition of T:T mismatch by echinomycin causes structural distortions in DNA duplex||作者:||Wu, Pei-Ching
Waring, Michael J
|關鍵字:||Antibiotics, Antineoplastic;Base Pair Mismatch;Cell Survival;Crystallography, X-Ray;DNA;Echinomycin;HCT116 Cells;Humans;Intercalating Agents;Molecular Structure;Neoplasms;Nucleic Acid Conformation||Project:||Nucleic acids research, Volume 46, Issue 14, Page(s) 7396-7404.||摘要:||
Small-molecule compounds that target mismatched base pairs in DNA offer a novel prospective for cancer diagnosis and therapy. The potent anticancer antibiotic echinomycin functions by intercalating into DNA at CpG sites. Surprisingly, we found that the drug strongly prefers to bind to consecutive CpG steps separated by a single T:T mismatch. The preference appears to result from enhanced cooperativity associated with the binding of the second echinomycin molecule. Crystallographic studies reveal that this preference originates from the staggered quinoxaline rings of the two neighboring antibiotic molecules that surround the T:T mismatch forming continuous stacking interactions within the duplex. These and other associated changes in DNA conformation allow the formation of a minor groove pocket for tight binding of the second echinomycin molecule. We also show that echinomycin displays enhanced cytotoxicity against mismatch repair-deficient cell lines, raising the possibility of repurposing the drug for detection and treatment of mismatch repair-deficient cancers.
|Appears in Collections:||基因體暨生物資訊學研究所|
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