3P4D

Alternatingly modified 2'Fluoro RNA octamer f/rC4G4

Summary for 3P4D

• Entry DOI: 10.2210/pdb3p4d/pdb
• Related: 3P4B 3P4C
• Descriptor: 5'-R(*(CFZ)P*CP*(CFZ)P*CP*(GF2)P*GP*(GF2)P*G)-3' (2 entities in total)
• Functional Keywords: rna, 2'-fluoro-rna, o2'-modification, octamer, 2'-fluoro 2'-deoxycytidine, 2'-fluoro 2'-deoxyguanosine, sirna
• Total number of polymer chains: 2
• Total formula weight: 5129.11

Authors

Pallan, P.S.,Greene, E.M.,Jicman, P.A.,Pandey, R.K.,Manoharan, M.,Rozners, E.,Egli, M. (deposition date: 2010-10-06, release date: 2011-01-05, Last modification date: 2023-09-06)

Primary citation

Pallan, P.S.,Greene, E.M.,Jicman, P.A.,Pandey, R.K.,Manoharan, M.,Rozners, E.,Egli, M.
Unexpected origins of the enhanced pairing affinity of 2'-fluoro-modified RNA.
Nucleic Acids Res., 39:3482-3495, 2011

PubMed Abstract: Various chemical modifications are currently being evaluated for improving the efficacy of short interfering RNA (siRNA) duplexes as antisense agents for gene silencing in vivo. Among the 2'-ribose modifications assessed to date, 2'deoxy-2'-fluoro-RNA (2'-F-RNA) has unique properties for RNA interference (RNAi) applications. Thus, 2'-F-modified nucleotides are well tolerated in the guide (antisense) and passenger (sense) siRNA strands and the corresponding duplexes lack immunostimulatory effects, enhance nuclease resistance and display improved efficacy in vitro and in vivo compared with unmodified siRNAs. To identify potential origins of the distinct behaviors of RNA and 2'-F-RNA we carried out thermodynamic and X-ray crystallographic analyses of fully and partially 2'-F-modified RNAs. Surprisingly, we found that the increased pairing affinity of 2'-F-RNA relative to RNA is not, as commonly assumed, the result of a favorable entropic contribution ('conformational preorganization'), but instead primarily based on enthalpy. Crystal structures at high resolution and osmotic stress demonstrate that the 2'-F-RNA duplex is less hydrated than the RNA duplex. The enthalpy-driven, higher stability of the former hints at the possibility that the 2'-substituent, in addition to its important function in sculpting RNA conformation, plays an underappreciated role in modulating Watson-Crick base pairing strength and potentially π-π stacking interactions.

PubMed: 21183463
DOI: 10.1093/nar/gkq1270

Experimental method

X-RAY DIFFRACTION (1.85 Å)