Solution structure of a 2:1 complex of anticancer drug XR5944 with TFF1 estrogen response element: insights into DNA recognition by a bis-intercalator

• Type of Material: Article
• Authors: Clement Lin, University of Arizona; Raveendra I. Mathad, University of Arizona; Zhenjiang Zhang, University of Arizona; Neil Sidell, Emory University; Danzhou Yang, University of Arizona
• Language: English
• Date: 2014-01-01
• Publisher: Oxford University Press (OUP): Policy C - Option B
• Publication Version: Final Published Version
• Copyright Statement: © 2014 The Author(s) 2014.
• License: Creative Commons Attribution 3.0 Unported
• Final Published Version (URL): http://dx.doi.org/10.1093/nar/gku219
• Title of Journal or Parent Work: Nucleic Acids Research
• ISSN: 0305-1048
• Volume: 42
• Issue: 9
• Start Page: 6012
• End Page: 6024
• Grant/Funding Information: National Institutes of Health [CA129424, 1S10 RR16659, 1K01CA83886].
• Keywords: BIOLOGICAL-ACTIVITY; TRANSCRIPTION; BINDING; HALF-SITES; Life Sciences & Biomedicine; Science & Technology; TELOMERIC G-QUADRUPLEX; RECEPTOR-ALPHA; NUCLEOTIDE SPACER SEQUENCE; BIOCHEMISTRY & MOLECULAR BIOLOGY; BREAST-CANCER; ANTITUMOR-ACTIVITY; Biochemistry & Molecular Biology; AROMATASE INHIBITORS
• Research Categories: Health Sciences, Pharmacy; Health Sciences, Obstetrics and Gynecology; Chemistry, General

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.