Summary information and primary citation
- PDB-id
-
5ytz;
DSSR-derived features in text and
JSON formats
- Class
- antibiotic-DNA
- Method
- X-ray (1.55 Å)
- Summary
- Crystal structure of echinomycin-d(acgtcgt)2
complex
- Reference
-
Wu PC, Tzeng SL, Chang CK, Kao YF, Waring MJ, Hou MH
(2018): "Cooperative
recognition of T:T mismatch by echinomycin causes
structural distortions in DNA duplex." Nucleic
Acids Res., 46, 7396-7404. doi:
10.1093/nar/gky345.
- Abstract
- 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.
