1XUX

Structural rationalization of a large difference in RNA affinity despite a small difference in chemistry between two 2'-O-modified nucleic acid analogs

1XUX の概要

• エントリーDOI: 10.2210/pdb1xux/pdb
• 分子名称: DNA (5'-D(*GP*CP*GP*TP*AP*(NMS)P*AP*CP*GP*C)-3') (2 entities in total)
• 機能のキーワード: rna mimetic methylamino amide analog, dna
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 12528.33

構造登録者

Pattanayek, R.,Sethaphong, L.,Pan, C.,Prhavc, M.,Prakash, T.P.,Manoharan, M.,Egli, M. (登録日: 2004-10-26, 公開日: 2004-12-14, 最終更新日: 2023-08-23)

主引用文献

Pattanayek, R.,Sethaphong, L.,Pan, C.,Prhavc, M.,Prakash, T.P.,Manoharan, M.,Egli, M.
Structural rationalization of a large difference in RNA affinity despite a small difference in chemistry between two 2'-O-modified nucleic acid analogues.
J.Am.Chem.Soc., 126:15006-15007, 2004

PubMed Abstract: Chemical modification of nucleic acids at the 2'-position of ribose has generated antisense oligonucleotides (AONs) with a range of desirable properties. Electron-withdrawing substituents such as 2'-O-[2-(methoxy)ethyl] (MOE) confer enhanced RNA affinity relative to that of DNA by conformationally preorganizing an AON for pairing with the RNA target and by improving backbone hydration. 2'-Substitution of the ribose has also been shown to increase nuclease resistance and cellular uptake via changes in lipophilicity. Interestingly, incorporation of either 2'-O-[2-(methylamino)-2-oxoethyl]- (NMA) or 2'-O-(N-methylcarbamate)-modified (NMC) residues into AONs has divergent effects on RNA affinity. Incorporation of 2'-O-NMA-T considerably improves RNA affinity while incorporation of 2'-O-NMC-T drastically reduces RNA affinity. Crystal structures at high resolution of A-form DNA duplexes containing either 2'-O-NMA-T or 2'-O-NMC-T shed light on the structural origins of the surprisingly large difference in stability given the relatively minor difference in chemistry between NMA and NMC. NMA substituents adopt an extended conformation and use either their carbonyl oxygen or amino nitrogen to trap water molecules between phosphate group and sugar. The conformational properties of NMA and the observed hydration patterns are reminiscent of those found in the structures of 2'-O-MOE-modified RNA. Conversely, the carbonyl oxygen of NMC and O2 of T are in close contact, providing evidence that an unfavorable electrostatic interaction and the absence of a stable water structure are the main reasons for the loss in thermodynamic stability as a result of incorporation of 2'-O-NMC-modified residues.

PubMed: 15547979
DOI: 10.1021/ja044637k

実験手法

X-RAY DIFFRACTION (1.3 Å)