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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
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 ((N)U) or 5-(N-aminohexyl)carbamoyl-2′-O-methyluridin...
Autores principales: | , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
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Oxford University Press
2007
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1874594/ https://www.ncbi.nlm.nih.gov/pubmed/17341465 http://dx.doi.org/10.1093/nar/gkl821 |
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author | Juan, Ella Czarina Magat Kondo, Jiro Kurihara, Takeshi Ito, Takanori Ueno, Yoshihito Matsuda, Akira Takénaka, Akio |
author_facet | Juan, Ella Czarina Magat Kondo, Jiro Kurihara, Takeshi Ito, Takanori Ueno, Yoshihito Matsuda, Akira Takénaka, Akio |
author_sort | Juan, Ella Czarina Magat |
collection | PubMed |
description | 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 ((N)U) or 5-(N-aminohexyl)carbamoyl-2′-O-methyluridine ((N)U(m)), respectively exhibit increased binding affinity for DNA and RNA, and enhanced nuclease resistance. To understand the structural implications of (N)U and (N)U(m) substitutions, we have determined the X-ray crystal structures of DNA:DNA duplexes containing either (N)U or (N)U(m) and of DNA:RNA hybrid duplexes containing (N)U(m). 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 (N)U, (N)U(m) 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 (N)U(m) containing DNA:DNA duplex structure. The conformation of (N)U(m), however, is compatible with the preferred conformation in DNA:RNA hybrid duplexes. Furthermore, the ability of (N)U(m) to render the duplexes with altered minor grooves may increase nuclease resistance and elicit RNase H activity. |
format | Text |
id | pubmed-1874594 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2007 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-18745942007-05-23 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 Juan, Ella Czarina Magat Kondo, Jiro Kurihara, Takeshi Ito, Takanori Ueno, Yoshihito Matsuda, Akira Takénaka, Akio Nucleic Acids Res Structural Biology 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 ((N)U) or 5-(N-aminohexyl)carbamoyl-2′-O-methyluridine ((N)U(m)), respectively exhibit increased binding affinity for DNA and RNA, and enhanced nuclease resistance. To understand the structural implications of (N)U and (N)U(m) substitutions, we have determined the X-ray crystal structures of DNA:DNA duplexes containing either (N)U or (N)U(m) and of DNA:RNA hybrid duplexes containing (N)U(m). 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 (N)U, (N)U(m) 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 (N)U(m) containing DNA:DNA duplex structure. The conformation of (N)U(m), however, is compatible with the preferred conformation in DNA:RNA hybrid duplexes. Furthermore, the ability of (N)U(m) to render the duplexes with altered minor grooves may increase nuclease resistance and elicit RNase H activity. Oxford University Press 2007-03 2007-03-06 /pmc/articles/PMC1874594/ /pubmed/17341465 http://dx.doi.org/10.1093/nar/gkl821 Text en © 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. |
spellingShingle | Structural Biology Juan, Ella Czarina Magat Kondo, Jiro Kurihara, Takeshi Ito, Takanori Ueno, Yoshihito Matsuda, Akira Takénaka, Akio 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 |
title | 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 |
title_full | 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 |
title_fullStr | 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 |
title_full_unstemmed | 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 |
title_short | 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 |
title_sort | 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 |
topic | Structural Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1874594/ https://www.ncbi.nlm.nih.gov/pubmed/17341465 http://dx.doi.org/10.1093/nar/gkl821 |
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