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Nucleic Acids Research Advance Access originally published online on March 6, 2007
Nucleic Acids Research 2007 35(6):1969-1977; doi:10.1093/nar/gkl821
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Nucleic Acids Research, 2007, Vol. 35, No. 6 1969-1977
© The Author 2006. Published by Oxford University Press. All rights reserved
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Structural Biology

Crystal structures of DNA:DNA and DNA:RNA duplexes containing 5-(N-aminohexyl)carbamoyl-modified uracils reveal the basis for properties as antigene and antisense molecules

Ella Czarina Magat Juan, Jiro Kondo, Takeshi Kurihara, Takanori Ito1, Yoshihito Ueno2, Akira Matsuda1 and Akio Takénaka*

Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama 226-8501, Japan, 1Graduate School of Pharmaceutical Sciences, Hokkaido Universitym, Sapporo 060-0812, Japan and 2Faculty of Engineering, Gifu University, Gifu 501-1193, Japan

*To whom correspondence should be addressed. Tel: +81 45 924 5709; Fax: +81 45 924 5748; Email: atakenak{at}bio.titech.ac.jp

Received July 26, 2006. Revised September 8, 2006. Accepted October 5, 2006.

Oligonucleotides containing 5-(N-aminohexyl)carbamoyl-modified uracils have promising features for applications as antigene and antisense therapies. Relative to unmodified DNA, oligonucleotides containing 5-(N-aminohexyl)carbamoyl-2'-deoxyuridine (NU) or 5-(N-aminohexyl)carbamoyl-2'-O-methyluridine (NUm), respectively exhibit increased binding affinity for DNA and RNA, and enhanced nuclease resistance. To understand the structural implications of NU and NUm substitutions, we have determined the X-ray crystal structures of DNA:DNA duplexes containing either NU or NUm and of DNA:RNA hybrid duplexes containing NUm. The aminohexyl chains are fixed in the major groove through hydrogen bonds between the carbamoyl amino groups and the uracil O4 atoms. The terminal ammonium cations on these chains could interact with the phosphate oxygen anions of the residues in the target strands. These interactions partly account for the increased target binding affinity and nuclease resistance. In contrast to NU, NUm decreases DNA binding affinity. This could be explained by the drastic changes in sugar puckering and in the minor groove widths and hydration structures seen in the NUm containing DNA:DNA duplex structure. The conformation of NUm, however, is compatible with the preferred conformation in DNA:RNA hybrid duplexes. Furthermore, the ability of NUm to render the duplexes with altered minor grooves may increase nuclease resistance and elicit RNase H activity.

Present address: Jiro Kondo, Institut de Biologie Moléculaire et Cellulaire du CNRS, Université Louis Pasteur, Strasbourg 67084, France


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