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Extension of sequence-specific recognition in the minor groove of DNA by pyrrole-imidazole polyamides to 9-13 base pairs

Trauger, John W. and Baird, Eldon E. and Mrksich, Milan and Dervan, Peter B. (1996) Extension of sequence-specific recognition in the minor groove of DNA by pyrrole-imidazole polyamides to 9-13 base pairs. Journal of the American Chemical Society, 118 (26). pp. 6160-6166. ISSN 0002-7863. http://resolver.caltech.edu/CaltechAUTHORS:20160510-103148152

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Abstract

The sequence-specific recognition of the minor groove of DNA by pyrrole−imidazole polyamides has been extended to 9−13 base pairs (bp). Four polyamides, ImPyPy-Py-PyPyPy-Dp, ImPyPy-G-PyPyPy-Dp, ImPyPy-β-PyPyPy-Dp, and ImPyPy-γ-PyPyPy-Dp (Im = N-methylimidazole, Py = N-methylpyrrole, Dp = N,N-dimethylaminopropylamide, G = glycine, β = β-alanine, and γ = γ-aminobutyric acid), were synthesized and characterized with respect to their DNA-binding affinities and specificities at sequences of composition 5‘-(A,T)G(A,T)_5C(A,T)-3‘ (9 bp) and 5‘-(A,T)_5G(A,T)C(A,T)_5-3‘ (13 bp). In both sequence contexts, the β-alanine-linked compound ImPyPy-β-PyPyPy-Dp has the highest binding affinity of the four polyamides, binding the 9 bp site 5‘-TGTTAAACA-3‘ (K_a = 8 × 10^8 M^(-1)) and the 13 bp site 5‘-AAAAAGACAAAAA-3‘ (K_a = 5 × 10^9 M^(-1)) with affinities higher than the formally N-methylpyrrole-linked polyamide ImPyPy-Py-PyPyPy-Dp by factors of ∼8 and ∼85, respectively (10 mM Tris·HCl, 10 mM KCl, 10 mM MgCl_2, and 5 mM CaCl_2, pH 7.0). The binding data for ImPyPy-γ-PyPyPy-Dp, which has been shown previously to bind DNA in a “hairpin” conformation, indicates that γ-aminobutyric acid does not effectively link polyamide subunits in an extended conformation. These results expand the binding site size targetable with pyrrole−imidazole polyamides and provide structural elements that will facilitate the design of new polyamides targeted to other DNA sequences.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1021/ja960726oDOIArticle
http://pubs.acs.org/doi/abs/10.1021/ja960726oPublisherArticle
Additional Information:© 1996 American Chemical Society. Received March 6, 1996. Abstract published in Advance ACS Abstracts, June 15, 1996. We are grateful to the National Institutes of Health (Grant GM-27681) for research support, to the National Science Foundation for a predoctoral fellowship to J.W.T., and to the Howard Hughes Medical Institute for a predoctoral fellowship to E.E.B.
Funders:
Funding AgencyGrant Number
NIHGM-27681
NSF Predoctoral FellowshipUNSPECIFIED
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
Record Number:CaltechAUTHORS:20160510-103148152
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:20160510-103148152
Official Citation:Extension of Sequence-Specific Recognition in the Minor Groove of DNA by Pyrrole−Imidazole Polyamides to 9−13 Base Pairs John W. Trauger, Eldon E. Baird, Milan Mrksich, and Peter B. Dervan Journal of the American Chemical Society 1996 118 (26), 6160-6166 DOI: 10.1021/ja960726o
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:66886
Collection:CaltechAUTHORS
Deposited By: Victoria Brennan
Deposited On:18 May 2016 21:07
Last Modified:18 May 2016 21:07

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