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PDBsum entry 3p4c
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References listed in PDB file
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Key reference
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Title
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Unexpected origins of the enhanced pairing affinity of 2'-Fluoro-Modified RNA.
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Authors
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P.S.Pallan,
E.M.Greene,
P.A.Jicman,
R.K.Pandey,
M.Manoharan,
E.Rozners,
M.Egli.
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Ref.
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Nucleic Acids Res, 2011,
39,
3482-3495.
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PubMed id
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Abstract
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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.
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Headers
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