5D8T

RNA octamer containing (S)-5' methyl, 2'-F U.

5D8T の概要

• エントリーDOI: 10.2210/pdb5d8t/pdb
• 分子名称: RNA oligonucleotide containing (S)-C5'-Me-2'-FU, COBALT HEXAMMINE(III) (3 entities in total)
• 機能のキーワード: rna, modified base
• 由来する生物種: synthetic construct
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 5887.41

構造登録者

Harp, J.M.,Egli, M. (登録日: 2015-08-17, 公開日: 2016-06-29, 最終更新日: 2024-03-06)

主引用文献

Kel In, A.V.,Zlatev, I.,Harp, J.,Jayaraman, M.,Bisbe, A.,O Shea, J.,Taneja, N.,Manoharan, R.M.,Khan, S.,Charisse, K.,Maier, M.A.,Egli, M.,Rajeev, K.G.,Manoharan, M.
Structural Basis of Duplex Thermodynamic Stability and Enhanced Nuclease Resistance of 5'-C-Methyl Pyrimidine-Modified Oligonucleotides.
J.Org.Chem., 81:2261-2279, 2016

PubMed Abstract: Although judicious use of chemical modifications has contributed to the success of nucleic acid therapeutics, poor systemic stability remains a major hurdle. The introduction of functional groups around the phosphate backbone can enhance the nuclease resistance of oligonucleotides (ONs). Here, we report the synthesis of enantiomerically pure (R)- and (S)-5'-C-methyl (C5'-Me) substituted nucleosides and their incorporation into ONs. These modifications generally resulted in a decrease in thermal stability of oligonucleotide (ON) duplexes in a manner dependent on the stereoconfiguration at C5' with greater destabilization characteristic of (R)-epimers. Enhanced stability against snake venom phosphodiesterase resulted from modification of the 3'-end of an ON with either (R)- or (S)-C5'-Me nucleotides. The (S)-isomers with different 2'-substituents provided greater resistance against 3'-exonucleases than the corresponding (R)-isomers. Crystal structure analyses of RNA octamers with (R)- or (S)-5'-C-methyl-2'-deoxy-2'-fluorouridine [(R)- or (S)-C5'-Me-2'-FU, respectively] revealed that the stereochemical orientation of the C5'-Me and the steric effects that emanate from the alkyl substitution are the dominant determinants of thermal stability and are likely molecular origins of resistance against nucleases. X-ray and NMR structural analyses showed that the (S)-C5'-Me epimers are spatially and structurally more similar to their natural 5' nonmethylated counterparts than the corresponding (R)-epimers.

PubMed: 26940174
DOI: 10.1021/acs.joc.5b02375

実験手法

X-RAY DIFFRACTION (1.2 Å)