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Recognition of seven base pair sequences in the minor groove of DNA by ten-ring pyrrole-imidazole polyamide hairpins

Turner, James M. and Baird, Eldon E. and Dervan, Peter B. (1997) Recognition of seven base pair sequences in the minor groove of DNA by ten-ring pyrrole-imidazole polyamide hairpins. Journal of the American Chemical Society, 119 (33). pp. 7636-7644. ISSN 0002-7863. doi:10.1021/ja971208w.

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A new upper limit of binding site size is defined for the hairpin polyamide-DNA motif. Ten-ring hairpin polyamides containing pyrrole (Py) and imidazole (Im) amino acids were designed for recognition of seven base pair (bp) sequences in the minor groove of DNA. The DNA binding properties of two polyamides, ImPyPyPyPy-γ-ImPyPyPyPy-β-Dp, and ImImPyPyPy-γ-ImPyPyPyPy-β-Dp were analyzed by footprinting and affinity cleavage on a DNA fragment containing the respective match sites 5‘-TGTAACA-3‘ and 5‘-TGGAACA-3‘. Quantitative footprint titrations demonstrate that ImPyPyPyPy-γ-ImPyPyPyPy-β-Dp binds the 7-bp match sequence 5‘-TGTAACA-3‘ with an equilibrium association constant (K_a) of K_a = 1.2 × 10^(10) M^(-1) and 18-fold specificity versus the single base pair mismatch sequence 5‘-TGGAACA-3‘. ImImPyPyPy-γ-ImPyPyPyPy-β-Dp differs from ImPyPyPyPy-γ-ImPyPyPyPy-β-Dp by a single amino acid substitution and binds its match 5‘-TGGAACA-3‘ site with K_a = 3.6 × 10^9 M^(-1) and 300-fold specificity versus its corresponding single base pair mismatch sequence 5‘-TGTAACA-3‘. Ten-ring hairpin polyamides have binding affinities similar to those of eight-ring hairpin polyamides. These results indicate that the affinity of hairpin binding ceases to increase as the length of the polyamide subunits increases beyond four rings, analogous to the behavior of unlinked subunits. Therefore, recognition of seven base pairs by a ten-ring hairpin polyamide most likely represents an upper limit to the effective targetable site size of the hairpin polyamide-DNA motif.

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Dervan, Peter B.0000-0001-8852-7306
Additional Information:© 1997 American Chemical Society. Received April 16, 1997. Publication Date (Web): August 20, 1997. Abstract published in Advance ACS Abstracts, August 1, 1997. We are grateful to the National Institutes of Health (GM-27681) for research support, J. Edward Richter for an undergraduate fellowship to J.M.T., 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.
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J. Edward RichterUNSPECIFIED
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
Issue or Number:33
Record Number:CaltechAUTHORS:20160510-101150499
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Official Citation:Recognition of Seven Base Pair Sequences in the Minor Groove of DNA by Ten-Ring Pyrrole−Imidazole Polyamide Hairpins James M. Turner, Eldon E. Baird, and Peter B. Dervan Journal of the American Chemical Society 1997 119 (33), 7636-7644 DOI: 10.1021/ja971208w
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:66873
Deposited By: Victoria Brennan
Deposited On:18 May 2016 20:54
Last Modified:11 Nov 2021 00:23

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