Recognition in the Minor Groove of DNA at 5'-(A,T)GCGC(A,T)-3 by a Four Ring Tripeptide Dimer. Reversal of the Specificity of the Natural Product Distamycin

Milan Mrksich, Peter B. Dervan*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

68 Scopus citations

Abstract

The tripeptide ImPImP containing alternating imidazole and pyrrole carboxamides specifically binds the designated six base pair site 5'-d(A,T)GCGC(A,T)-3 in the minor groove of DNA. Quantitative footprint titration experiments demonstrate that ImPImP binds the sites 5'-AGCGCT-3 and 5'-TGCGCA-3 with apparent first order binding affinities of 3.8 ×105M-1 and 3.6 × 105M-1, respectively (25 mM tris acetate, 10 mM NaCl, pH 7.0 and 22 °C). Affinity cleaving experiments with ImPImP-EDTA·Fe reveals equal cleavage on both sides of the 5'-(A,T)-GCGC(A,T)-3 site, consistent with a side-by-side antiparallel arrangement of the four ring peptides in the minor groove. This reversal of specificity of the natural product distamycin which prefers to bind pure A,T sequences underscores the utility of 2:1 peptide—DNA models for the design of ligands for sequence-specific recognition in the minor groove of DNA. By extending these peptides to four ring systems, a new lower limit of six base pair binding by 2:1 peptide-DNA complexes has been defined.

Original languageEnglish (US)
Pages (from-to)3325-3332
Number of pages8
JournalJournal of the American Chemical Society
Volume117
Issue number12
DOIs
StatePublished - Mar 1995

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

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