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Recognition of a 5‘-(A,T)GGG(A,T)_2-3‘ Sequence in the Minor Groove of DNA by an Eight-Ring Hairpin Polyamide

Swalley, Susanne E. and Baird, Eldon E. and Dervan, Peter B. (1996) Recognition of a 5‘-(A,T)GGG(A,T)_2-3‘ Sequence in the Minor Groove of DNA by an Eight-Ring Hairpin Polyamide. Journal of the American Chemical Society, 118 (35). pp. 8198-8206. ISSN 0002-7863. http://resolver.caltech.edu/CaltechAUTHORS:20160510-102542329

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Abstract

The use of pyrrole−imidazole polyamides for the recognition of core 5‘-GGG-3‘ sequences in the minor groove of double stranded DNA is described. Two hairpin pyrrole−imidazole polyamides, ImImIm-γ-PyPyPy-β-Dp and ImImImPy-γ-PyPyPyPy-β-Dp (Im = N-methylimidazole-2-carboxamide, Py = N-methylpyrrole-2-carboxamide, β = β-alanine, γ = γ-aminobutyric acid, and Dp = ((dimethylamino)propyl)amide), as well as the corresponding EDTA affinity cleaving derivatives, were synthesized and their DNA binding properties analyzed. Quantitative DNase I footprint titrations demonstrate that ImImIm-γ-PyPyPy-β-Dp binds the formal match sequence 5‘-AGGGA-3‘ with an equilibrium association constant of K_a = 5 × 10^6 M^(-1) (10 mM Tris·HCl, 10 mM KCl, 10 mM MgCl_2, and 5 mM CaCl_2, pH 7.0 and 22 °C). ImImImPy-γ-PyPyPyPy-β-Dp binds the same site, 5‘-AGGGAA-3‘, approximately two orders of magnitude more tightly than the six ring polyamide, with an equilibrium association constant of K_a = 4 × 10^8 M^(-1). The eight-ring hairpin polyamide demonstrates greater specifity for single base pair mismatches than does the six ring hairpin. Polyamides with an EDTA·Fe(II) moiety at the carboxy terminus confirm that each hairpin binds in a single orientation. The high affinity recognition of a 5‘-GGG-3‘ core sequence by an eight ring polyamide containing three contiguous imidazole amino acids demonstrates the versatility of pyrrole−imidazole polyamides and broadens the sequence repertoire for DNA recognition.


Item Type:Article
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URLURL TypeDescription
http://dx.doi.org/10.1021/ja9611598DOIArticle
http://pubs.acs.org/doi/abs/10.1021/ja9611598PublisherArticle
Additional Information:© 1996 American Chemical Society. Received April 8, 1996; Publication Date (Web): September 4, 1996. This paper is dedicated to Nelson Leonard on the occasion of his 80th birthday. We are grateful to the National Institutes of Health (GM-2768) for research support, the National Institutes of Health for a research service award to S.E.S., and the Howard Hughes Medical Institute for a predoctoral fellowship to E.E.B. We would like to thank G. M. Hathaway for MALDI-TOF mass spectrometry.
Funders:
Funding AgencyGrant Number
NIHGM-27681
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
NIH Predoctoral FellowshipUNSPECIFIED
Record Number:CaltechAUTHORS:20160510-102542329
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:20160510-102542329
Official Citation:Recognition of a 5‘-(A,T)GGG(A,T)2-3‘ Sequence in the Minor Groove of DNA by an Eight-Ring Hairpin Polyamide Susanne E. Swalley, Eldon E. Baird, and Peter B. Dervan Journal of the American Chemical Society 1996 118 (35), 8198-8206 DOI: 10.1021/ja9611598
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:66883
Collection:CaltechAUTHORS
Deposited By: Victoria Brennan
Deposited On:18 May 2016 21:56
Last Modified:18 May 2016 21:56

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