2MG8

Solution structure of TFF1 Estrogen Response Element complexed with DNA Bis-intercalating Anticancer Drug XR5944 (MLN944)

Summary for 2MG8

• Entry DOI: 10.2210/pdb2mg8/pdb
• Related: 1X95
• NMR Information: BMRB: 19592
• Descriptor: 5'-D(*AP*GP*GP*TP*CP*AP*CP*GP*GP*TP*GP*GP*CP*CP*A)-3', 5'-D(*TP*GP*GP*CP*CP*AP*CP*CP*GP*TP*GP*AP*CP*CP*T)-3', 1-METHYL-9-[12-(9-METHYLPHENAZIN-10-IUM-1-YL)-12-OXO-2,11-DIAZA-5,8-DIAZONIADODEC-1-ANOYL]PHENAZIN-10-IUM (3 entities in total)
• Functional Keywords: breast cancer drug, dna bis-intercalation, ere-targeting small molecule anticancer drug, dna
• Total number of polymer chains: 2
• Total formula weight: 10362.39

Authors

Lin, C. (deposition date: 2013-10-30, release date: 2014-04-23, Last modification date: 2024-05-01)

Primary citation

Lin, C.,Mathad, R.I.,Zhang, Z.,Sidell, N.,Yang, D.
Solution structure of a 2:1 complex of anticancer drug XR5944 with TFF1 estrogen response element: insights into DNA recognition by a bis-intercalator.
Nucleic Acids Res., 42:6012-6024, 2014

PubMed Abstract: XR5944, a deoxyribonucleic acid (DNA) bis-intercalator with potent anticancer activity, can bind the estrogen response element (ERE) sequence to inhibit estrogen receptor-α activities. This novel mechanism of action may be useful for overcoming drug resistance to currently available antiestrogen treatments, all of which target the hormone-receptor complex. Here we report the nuclear magnetic resonance solution structure of the 2:1 complex of XR5944 with the naturally occurring TFF1-ERE, which exhibits important and unexpected features. In both drug-DNA complexes, XR5944 binds strongly at one intercalation site but weakly at the second site. The sites of intercalation within a native promoter sequence appear to be context and sequence dependent. The binding of one drug molecule influences the binding site of the second. Our structures underscore the fact that the DNA binding of a bis-intercalator is directional and different from the simple addition of two single intercalation sites. Our study suggests that improved XR5944 bis-intercalators targeting ERE may be designed through optimization of aminoalkyl linker and intercalation moieties at the weak binding sites.

PubMed: 24711371
DOI: 10.1093/nar/gku219

Experimental method

SOLUTION NMR