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Sequence selectivity of 3-hydroxypyrrole/pyrrole ring pairings in the DNA minor groove

Urbach, Adam R. and Szewczyk, Jason W. and White, Sarah and Turner, James M. and Baird, Eldon E. and Dervan, Peter B. (1999) Sequence selectivity of 3-hydroxypyrrole/pyrrole ring pairings in the DNA minor groove. Journal of the American Chemical Society, 121 (50). pp. 11621-11629. ISSN 0002-7863.

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Hairpin polyamides containing the aromatic amino acids 3-hydroxypyrrole (Hp), pyrrole (Py), and imidazole (Im) are capable of discriminating all four Watson−Crick base pairs in the DNA minor groove according to a set of pairing rules. Equilibrium association constants for four eight-ring hairpins containing all four pairings of Hp and Py at a single common position (ImImXPy-γ-ImYPyPy-β-Dp, where X/Y is Py/Py, Py/Hp, Hp/Py, and Hp/Hp) were determined at four DNA sites, 5‘-TGGTCA-3‘, 5‘-TGGACA-3‘, 5‘-TGGCCA-3‘, and 5‘-TGGGCA-3‘, to study the relative binding affinities of the 16 possible complexes. The protected 3-hydroxypyrrole amino acid building block, 3-methoxypyrrole, is prepared on a 50 g scale, and the solid-phase synthesis of hydroxypyrrole−imidazole−pyrrole polyamides is described. Quantitative DNase I footprint titrations demonstrate that a Py/Py pair is partially degenerate for A•T and T•A, but disfavors G•C and C•G base pairs by 53- and 17-fold, respectively. An Hp/Py pair placed opposite T•A binds at least 20-fold more tightly than when placed opposite A•T, G•C, and C•G base pairs. The Py/Hp pair selectively binds A•T with 11-fold higher affinity over T•A and with ≥30-fold selectivity relative to G•C and C•G. An Hp/Hp pairing is disfavored opposite all four base pairs, potentially limiting certain slipped motifs available to unlinked dimers in the minor groove. This study serves to guide the design of second-generation polyamides for DNA recognition.

Item Type:Article
Dervan, Peter B.0000-0001-8852-7306
Additional Information:© 1999 American Chemical Society. Received August 23, 1999. Publication Date (Web): December 1, 1999. We are grateful to the National Institutes of Health (GM-27681) for research support, National Institutes of Health for a research service award to J.W.S and S.W., J. Edward Richter for an undergraduate fellowship to J.M.T., the National Science Foundation for a predoctoral fellowship to A.R.U., and the Howard Hughes Medical Institute for a predoctoral fellowship to E.E.B. We thank G. M. Hathaway for MALDI-TOF mass spectrometry.
Funding AgencyGrant Number
NIH Predoctoral FellowshipUNSPECIFIED
J. Edward RichterUNSPECIFIED
NSF Predoctoral FellowshipUNSPECIFIED
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
Issue or Number:50
Record Number:CaltechAUTHORS:20160510-085348881
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Official Citation:Sequence Selectivity of 3-Hydroxypyrrole/Pyrrole Ring Pairings in the DNA Minor Groove Adam R. Urbach, Jason W. Szewczyk, Sarah White, James M. Turner, Eldon E. Baird, and Peter B. Dervan Journal of the American Chemical Society 1999 121 (50), 11621-11629 DOI: 10.1021/ja9930667
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:66841
Deposited By: Victoria Brennan
Deposited On:18 May 2016 19:59
Last Modified:11 Nov 2021 00:22

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