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1y7f

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{{STRUCTURE_1y7f| PDB=1y7f | SCENE= }}
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'''Crystal structure of the A-DNA GCGTAT*CGC with a 2'-O-[2-[hydroxy(methyleneamino)oxy]ethyl] Thymidine (T*)'''
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===Crystal structure of the A-DNA GCGTAT*CGC with a 2'-O-[2-[hydroxy(methyleneamino)oxy]ethyl] Thymidine (T*)===
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==Overview==
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The syntheses of 10 new RNA 2'-O-modifications, their incorporation into oligonucleotides, and an evaluation of their properties such as RNA affinity and nuclease resistance relevant to antisense activity are presented. All modifications combined with the natural phosphate backbone lead to significant gains in terms of the stability of hybridization to RNA relative to the first-generation DNA phosphorothioates (PS-DNA). The nuclease resistance afforded in particular by the 2'-O-modifications carrying a positive charge surpasses that of PS-DNA. However, small electronegative 2'-O-substituents, while enhancing the RNA affinity, do not sufficiently protect against degradation by nucleases. Similarly, oligonucleotides containing 3'-terminal residues modified with the relatively large 2'-O-[2-(benzyloxy)ethyl] substituent are rapidly degraded by exonucleases, proving wrong the assumption that steric bulk will generally improve protection against nuclease digestion. To analyze the factors that contribute to the enhanced RNA affinity and nuclease resistance we determined crystal structures of self-complementary A-form DNA decamer duplexes containing single 2'-O-modified thymidines per strand. Conformational preorganization of substituents, favorable electrostatic interactions between substituent and sugar-phosphate backbone, and a stable water structure in the vicinity of the 2'-O-modification all appear to contribute to the improved RNA affinity. Close association of positively charged substituents and phosphate groups was observed in the structures with modifications that protect most effectively against nucleases. The promising properties exhibited by some of the analyzed 2'-O-modifications may warrant a more detailed evaluation of their potential for in vivo antisense applications. Chemical modification of RNA can also be expected to significantly improve the efficacy of small interfering RNAs (siRNA). Therefore, the 2'-O-modifications introduced here may benefit the development of RNAi therapeutics.
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==About this Structure==
==About this Structure==
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Jul 27 12:21:36 2008''

Revision as of 09:21, 27 July 2008

Image:1y7f.png

Template:STRUCTURE 1y7f

Crystal structure of the A-DNA GCGTAT*CGC with a 2'-O-[2-[hydroxy(methyleneamino)oxy]ethyl] Thymidine (T*)

Template:ABSTRACT PUBMED 15966728

About this Structure

Full crystallographic information is available from OCA.

Reference

Probing the influence of stereoelectronic effects on the biophysical properties of oligonucleotides: comprehensive analysis of the RNA affinity, nuclease resistance, and crystal structure of ten 2'-O-ribonucleic acid modifications., Egli M, Minasov G, Tereshko V, Pallan PS, Teplova M, Inamati GB, Lesnik EA, Owens SR, Ross BS, Prakash TP, Manoharan M, Biochemistry. 2005 Jun 28;44(25):9045-57. PMID:15966728

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