2G92

Crystal Structure Analysis of the RNA Dodecamer CGC-(NF2)-AAUUAGCG, with an Incorporated 2,4-Difluorotoluyl Residue (NF2)

Summary for 2G92

• Entry DOI: 10.2210/pdb2g92/pdb
• Descriptor: 5'-R(*CP*GP*CP*(NF2)P*AP*AP*UP*UP*AP*GP*CP*G)-3' (2 entities in total)
• Functional Keywords: 2, 4-difluorotoluyl nucleoside, chemical modification, rna, rna interference, hydrogen bonding
• Total number of polymer chains: 2
• Total formula weight: 7656.71

Authors

Egli, M.,Li, F. (deposition date: 2006-03-04, release date: 2006-04-18, Last modification date: 2024-04-03)

Primary citation

Xia, J.,Noronha, A.,Toudjarska, I.,Li, F.,Akinc, A.,Braich, R.,Frank-Kamenetsky, M.,Rajeev, K.G.,Egli, M.,Manoharan, M.
Gene silencing activity of siRNAs with a ribo-difluorotoluyl nucleotide.
Acs Chem.Biol., 1:176-183, 2006

PubMed Abstract: Recently, chemically synthesized short interfering RNA (siRNA) duplexes have been used with success for gene silencing. Chemical modification is desired for therapeutic applications to improve biostability and pharmacokinetic properties; chemical modification may also provide insight into the mechanism of silencing. siRNA duplexes containing the 2,4-difluorotoluyl ribonucleoside (rF) were synthesized to evaluate the effect of noncanonical nucleoside mimetics on RNA interference. 5'-Modification of the guide strand with rF did not alter silencing relative to unmodified control. Internal uridine to rF substitutions were well-tolerated. Thermal melting analysis showed that the base pair between rF and adenosine (A) was destabilizing relative to a uridine-adenosine pair, although it was slightly less destabilizing than other mismatches. The crystal structure of a duplex containing rFoA pairs showed local structural variations relative to a canonical RNA helix. As the fluorine atoms cannot act as hydrogen bond acceptors and are more hydrophobic than uridine, there was an absence of a well-ordered water structure around the rF residues in both grooves. siRNAs with the rF modification effectively silenced gene expression and offered improved nuclease resistance in serum; therefore, evaluation of this modification in therapeutic siRNAs is warranted.

PubMed: 17163665
DOI: 10.1021/cb600063p

Experimental method

X-RAY DIFFRACTION (1.61 Å)