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NMR characterization of hairpin polyamide complexes with the minor groove of DNA

Peláez Lamamie de Clairac, Rafael and Geierstanger, Bernhard H. and Mrksich, Milan and Dervan, Peter B. and Wemmer, David E. (1997) NMR characterization of hairpin polyamide complexes with the minor groove of DNA. Journal of the American Chemical Society, 119 (34). pp. 7909-7916. ISSN 0002-7863. doi:10.1021/ja964314r.

[img] PDF (Listings of the intermolecular ligand−DNA and ligand−ligand restraints and the achieved distances, and chemical shift assignments for the DNA and the ligands in the ImPyPy-γ-PyPyPy-Dp, ImPyPy-δ-PyPyPy-Dp and ImPyPy-β-PyPyPy-Dp complexes) - Supplemental Material
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Polyamides containing N-methylimidazole (Im) and N-methylpyrrole (Py) amino acids can be combined in antiparallel side-by-side dimeric complexes for sequence-specific recognition in the minor groove of DNA. Covalently linking polyamide subunits has led to designed ligands with both increased affinity and specificity. Simple aliphatic amino acid linkers serve as internal guide residues for turn vs extended binding in a head-to-tail-linked polyamide motif. Polyamides of sequence composition ImPyPy-X-PyPyPy containing linkers of incremental length (X = 3-aminopropionic acid (β), 4-aminobutyric acid (γ), or 5-aminovaleric acid (δ)) in complex with an undecamer DNA duplex containing a 5'-(A,T)G(A,T)(3)-3' target site were structurally characterized using NMR spectroscopy. Previous quantitative DNase I footprinting studies identified gamma as the highest affinity of these "turn" linkers. NMR titrations and 2D NOESY data combined with restrained molecular modeling reveal that polyamides with β, γ, and δ linkers all may adopt a hairpin structure. Modeling supports the idea that the linkers in the βand δcomplexes adopt an energetically less favorable turn geometry than the γlinker and confirms that the three-carbon γ linker is sufficient and optimal for the hairpin conformation.

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Dervan, Peter B.0000-0001-8852-7306
Additional Information:© 1997 American Chemical Society. Received December 16, 1996. Publication Date (Web): August 27, 1997. Abstract published in AdVance ACS Abstracts, August 15, 1997. We are grateful to National Institutes of Health (GM-43129 D.E.W. and GM-27681 P.B.D.) and the National Foundation for Cancer Research for research support, to the Ralph M. Parson Foundation for a graduate fellowship to M.M., and to the U.S. Department of Energy, National Science Foundation and Keck Foundation for instrumentation grants. R.P.L.deC. gratefully acknowledges a postdoctoral fellowship from the Fundación Ramón Areces. R.P.L.deC., B.H.G., and D.E.W. also thank T. D. Cole for helpful discussions and assistance in the early stages of the project.
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National Foundation for Cancer ResearchUNSPECIFIED
Ralph M. Parsons FoundationUNSPECIFIED
Department of Energy (DOE)UNSPECIFIED
W. M. Keck FoundationUNSPECIFIED
Fundación Ramón ArecesUNSPECIFIED
Issue or Number:34
Record Number:CaltechAUTHORS:20160510-101732280
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Official Citation:NMR Characterization of Hairpin Polyamide Complexes with the Minor Groove of DNA Rafael Peláez Lamamie de Clairac, Bernhard H. Geierstanger, Milan Mrksich, Peter B. Dervan, and David E. Wemmer Journal of the American Chemical Society 1997 119 (34), 7909-7916 DOI: 10.1021/ja964314r
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:66875
Deposited By: Victoria Brennan
Deposited On:18 May 2016 19:28
Last Modified:11 Nov 2021 00:23

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