411d

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spinqualitylabelsall models 411d, resolution 1.930Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

DUPLEX [5'-D(GCGTA+TACGC)]2 WITH INCORPORATED 2'-O-METHOXYETHYL RIBONUCLEOSIDE

Overview

Chemically modified nucleic acids are currently being evaluated as, potential antisense compounds for therapeutic applications. 2'-O-Ethylene, glycol substituted oligoribonucleotides are second-generation antisense, inhibitors of gene expression with promising features for in vivo use., Relative to DNA, they display improved RNA affinity and higher nuclease, resistance. Moreover, chimeric oligonucleotides with 2'-O-methoxyethyl, ribonucleoside wings and a central DNA phosphorothioate window have been, shown to effectively reduce the growth of tumors in animal models at low, doses. Using X-ray crystallography, we have determined the structures of, three A-form DNA duplexes containing the following 2'-O-modified, ribothymidine building blocks: 2'-O-methoxyethyl ribo-T, 2'-O-methyl[tri(oxyethyl)] ribo-T, and 2'-O-ethoxymethylene ribo-T. In, contrast to 2'-O-ethylene glycol substituents, the presence of a, 2'-O-ethoxymethylene group leads to slightly reduced RNA affinity of the, corresponding oligonucleotides. The three structures allow a qualitative, rationalization of the differing stabilities of duplexes between, oligonucleotides comprising these types of 2'-O-modified ribonucleotides, and complementary RNAs. The stabilizing 2'-O-ethylene glycol substituents, are conformationally preorganized for the duplex state. Thus, the presence, of one or several ethylene glycol moieties may reduce the conformational, space of the substituents in an oligonucleotide single strand. In, addition, most of these preferred conformations appear to be compatible, with the minor groove topology in an A-type duplex. Factors that, contribute to the conformational rigidity of the 2'-O-substituents are, anomeric and gauche effects, electrostatic interactions between backbone, and substituent, and bound water molecules.

About this Structure

411D is a Protein complex structure of sequences from [1]. Full crystallographic information is available from OCA.

Reference

Correlating structure and stability of DNA duplexes with incorporated 2'-O-modified RNA analogues., Tereshko V, Portmann S, Tay EC, Martin P, Natt F, Altmann KH, Egli M, Biochemistry. 1998 Jul 28;37(30):10626-34. PMID:9692952[[Category: duplex [5'-d(gcgta+tacgc)]2 with incorporated 2'-o-methoxyethyl ribonucleoside]]

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