Binding of AR-1-144, a tri-imidazole DNA minor groove binder, to CCGG sequence analyzed by NMR spectroscopy

Xiang Lei Yang, Crystal Kaenzig, Moses Lee, Andrew H.J. Wang

Research output: Contribution to journalArticlepeer-review

28 Citations (Scopus)

Abstract

The interactions of N-[2-(dimethylamino)ethyl]-1-methyl-4-[1-methyl-4- [4-formamido-1-methylimidazole-2-carboxamido]imidazole-2- carboxamido]imidazole-2-carboxamide (AR-1-144), a tri-imidazole polyamide minor groove binder, with DNA have been investigated by NMR and CD spectroscopy. A series of DNA oligonucleotides with a C/G-containing four-bp core, i.e. CCGG, CGCG, GGCC, and GCGC, have been titrated with AR-1-144 at different ratios. AR-1-144 favors the CCGG sequence. The flanking sequence of the CCGG core also influences the binding preference, with a C or T being favored on the 3'-side of the CCGG core. The three-dimensional structure of the symmetric 2: 1 side-by-side complex of AR-1-144 and GAACCGGTTC, determined by NOE-constrained NMR refinement, reveals that each AR-1-144 binds to four base pairs, i.e. at C5-G6-G7-T8, with every amide-imidazole unit forming two potential hydrogen bonds with DNA. The same DNA binding preference of AR-1-144 was also confirmed by circular dichroism spectroscopy, indicating that the DNA binding preference of AR-1-144 is independent of concentration. The cooperative binding of an AR-1-144 homodimer to the (purine)CCGG(pyrimidine) core sequence appears to be weaker than that of the distamycin A homodimer to A/T sequences, most likely due to the diminished hydrophobic interactions between AR-1-144 and DNA. Our results are consistent with previous footprinting data and explain the binding pattern found in the crystal structure of a di-imidazole drug bound to CATGGCCATG.

Original languageEnglish
Pages (from-to)646-655
Number of pages10
JournalEuropean Journal of Biochemistry
Volume263
Issue number3
DOIs
Publication statusPublished - Aug 1 1999
Externally publishedYes

Keywords

  • Anti-cancer drug
  • DNA structure
  • Drug design
  • Sequence specific recognition

ASJC Scopus subject areas

  • Biochemistry

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