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Discrimination of A/T sequences in the minor groove of DNA within a cyclic polyamide motif

Melander, Christian and Herman, David M. and Dervan, Peter B. (2000) Discrimination of A/T sequences in the minor groove of DNA within a cyclic polyamide motif. Chemistry: a European Journal, 6 (24). pp. 4487-97. ISSN 0947-6539. http://resolver.caltech.edu/CaltechAUTHORS:20160510-091106223

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Abstract

Eight-ring cyclic polyamides containing pyrrole (Py), imidazole (Im), and hydroxypyrrole (Hp) aromatic amino acids recognize predetermined six base pair sites in the minor groove of DNA. Two four-ring polyamide subunits linked by (R)-2,4-diaminobutyric acid [(R)γ] residue form hairpin polyamide structures with enhanced DNA binding properties. In hairpin polyamides, substitution of Hp/Py for Py/Py pairs enhances selectivity for T⋅A base pairs but compromises binding affinity for specific sequences. In an effort to enhance the binding properties of polyamides containing Hp/Py pairings, four eight ring cyclic polyamides were synthesized and analyzed on a DNA restriction fragment containing three 6-bp sites 5′-tAGNNCTt-3′, where NN=AA, TA, or AT. Quantitative footprint titration experiments demonstrate that contiguous placement of Hp/Py pairs in cyclo-(γ-ImPyPyPy-(R)γ-ImHpHpPy-) (1) provides a 20-fold increase in affinity for the 5′-tAGAACTt-3′ site (K_a=7.5×10^7 M^(−1)) relative to ImPyPyPy-(R)γ-ImHpHpPy-C3-OH (2). A cyclic polyamide of sequence composition cyclo-(γ-ImHpPyPy-(R)γ-ImHpPyPy-) (3) binds a 5′-tAGTACTt-3′ site with an equilibrium association constant K_a=3.2×10^9 M^(−1), representing a fivefold increase relative to the hairpin analogue ImHpPyPy-(R)γ-ImHpPyPy-C3-OH (4). Arrangement of Hp/Py pairs in a 3′-stagger regulates specificity of cyclo-(γ-ImPyHpPy-(R)γ-ImPyHpPy-) (5) for the 5′-tAGATCTt-3′ site (K_a=7.5×10^7 M^(−1)), threefold increase in affinity relative to the hairpin analogue ImPyHpPy-(R)γ-ImPyHpPy-C3-OH (6), respectively. This study identifies cyclic polyamides as a viable motif for restoring recognition properties of polyamides containing Hp/Py pairs.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1002/1521-3765(20001215)6:24<4487::AID-CHEM4487>3.0.CO;2-CDOIArticle
http://onlinelibrary.wiley.com/doi/10.1002/1521-3765(20001215)6:24%3C4487::AID-CHEM4487%3E3.0.CO;2-C/abstract;jsessionid=E8315EF01A758900E29651DE48047144.f04t02PublisherArticle
Additional Information:© 2000 Wiley-VCH Verlag GmbH, D-69451 Weinheim. Received: August 11, 2000. First published: 27 November 2000. We are grateful to the National Institutes of Health (GM-27681) for research support, the Treadway Foundation (Bio.47123-1-EN DOW.471230) for a research award to D.M.H., and the National Institutes of Health (GM19789-02) for a postdoctoral fellowship to C.M. We thank G. M. Hathaway for MALDI-TOF mass spectrometry and S. White for construction of pDEH10.
Funders:
Funding AgencyGrant Number
NIHGM-27681
Treadway FoundationBio.47123-1-ENDOW.471230
NIH Postdoctoral FellowshipGM19789-02
Record Number:CaltechAUTHORS:20160510-091106223
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:20160510-091106223
Official Citation:Melander, C., Herman, D. M. and Dervan, P. B. (2000), Discrimination of A/T Sequences in the Minor Groove of DNA within a Cyclic Polyamide Motif. Chem. Eur. J., 6: 4487–4497. doi:10.1002/1521-3765(20001215)6:24<4487::AID-CHEM4487>3.0.CO;2-C
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:66844
Collection:CaltechAUTHORS
Deposited By: Victoria Brennan
Deposited On:18 May 2016 20:24
Last Modified:18 May 2016 20:24

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