Solution structure of an arabinonucleic acid (ANA)/RNA duplex in a chimeric hairpin: comparison with 2'-fluoro-ANA/RNA and DNA/RNA hybrids.
Hybrids of RNA and arabinonucleic acid (ANA) as well as the 2'-fluoro-ANA analog (2'F-ANA) were recently shown to be substrates of the enzyme RNase H. Although RNase H binds to double-stranded RNA, no cleavage occurs with such duplexes. Therefore, knowledge of the structure of ANA/RNA hybrids may prove helpful in the design of future antisense oligonucleotide analogs. In this study, we have determined the NMR solution structures of ANA/RNA and DNA/RNA hairpin duplexes and compared them to the recently published structure of a 2'F-ANA/RNA hairpin duplex. We demonstrate here that the sugars of RNA nucleotides of the ANA/RNA hairpin stem adopt the C3'-endo (north, A-form) conformation, whereas those of the ANA strand adopt a 'rigid' O4'-endo (east) sugar pucker. The DNA strand of the DNA/RNA hairpin stem is flexible, but the average DNA/RNA hairpin structural parameters are close to the ANA/RNA and 2'F-ANA/RNA hairpin parameters. The minor groove width of ANA/RNA, 2'F-ANA/RNA and DNA/RNA helices is 9.0 +/- 0.5 A, a value that is intermediate between that of A- and B-form duplexes. These results rationalize the ability of ANA/RNA and 2'F-ANA/RNA hybrids to elicit RNase H activity.
Denisov
A Y
AY
Department of Biochemistry and Montreal Joint Centre for Structural Biology, McGill University, Montreal, QC H3G 1Y6, Canada.
Noronha
A M
AM
Wilds
C J
CJ
Trempe
J F
JF
Pon
R T
RT
Gehring
K
K
Damha
M J
MJ
D001088:Arabinonucleotides / Q000737:chemistry / Q000378:metabolism*; D001483:Base Sequence; D004247:DNA / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D009690:Nucleic Acid Conformation; D009692:Nucleic Acid Heteroduplexes / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D009841:Oligonucleotides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D018583:Pliability; D012313:RNA / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D020871:RNA Stability; D016914:Ribonuclease H / Q000378:metabolism; D012266:Ribose / Q000737:chemistry / Q000378:metabolism; D012996:Solutions; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013816:Thermodynamics
D001088:Arabinonucleotides; D009692:Nucleic Acid Heteroduplexes; D009841:Oligonucleotides; D012996:Solutions; D012313:RNA; D012266:Ribose; D004247:DNA; D016914:Ribonuclease H