5D8T

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

Summary for 5D8T

• Entry DOI: 10.2210/pdb5d8t/pdb
• Descriptor: RNA oligonucleotide containing (S)-C5'-Me-2'-FU, COBALT HEXAMMINE(III) (3 entities in total)
• Functional Keywords: rna, modified base
• Biological source: synthetic construct
• Total number of polymer chains: 2
• Total formula weight: 5887.41

Authors

Harp, J.M.,Egli, M. (deposition date: 2015-08-17, release date: 2016-06-29, Last modification date: 2024-03-06)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.2 Å)