PDBsum entry 469d

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Waters ×105
PDB id:
Name: RNA
Title: Crystal structure and improved antisense properties of 2'-o- methoxyethyl)-RNA
Structure: RNA (5'-r( (C43)p (G48)p (C43)p (G48)p (A44)p (A4 p (U36)p (C43)p (G48)p (C43)p (G48))-3'). Chain: a, b. Engineered: yes. Other_details: o2 Of each ribose modified by methoxyethyl
Source: Synthetic: yes
1.70Å     R-factor:   0.206     R-free:   0.258
Authors: M.Teplova,G.Minasov,V.Tereshko,G.Inamati,P.D.Cook,M.Egli
Key ref:
M.Teplova et al. (1999). Crystal structure and improved antisense properties of 2'-O-(2-methoxyethyl)-RNA. Nat Struct Biol, 6, 535-539. PubMed id: 10360355 DOI: 10.1038/9304
29-Apr-99     Release date:   12-May-99    


DOI no: 10.1038/9304 Nat Struct Biol 6:535-539 (1999)
PubMed id: 10360355  
Crystal structure and improved antisense properties of 2'-O-(2-methoxyethyl)-RNA.
M.Teplova, G.Minasov, V.Tereshko, G.B.Inamati, P.D.Cook, M.Manoharan, M.Egli.
2'-O-(2-Methoxyethyl)-RNA (MOE-RNA) is a nucleic acid analog with promising features for antisense applications. Compared with phosphorothioate DNA (PS-DNA), the MOE modification offers improved nuclease resistance, enhanced RNA affinity, improved cellular uptake and intestinal absorption, reduced toxicity and immune stimulation. The crystal structure of a fully modified MOE-RNA dodecamer duplex (CGCGAAUUCGCG) was determined at 1.7 A resolution. In the majority of the MOE substituents, the torsion angle around the ethylene alkyl chain assumes a gauche conformation. The conformational preorganization of the MOE groups is consistent with the improved RNA affinity and the extensive hydration of the substituents could play a role in the improved cellular uptake of MOE-RNA. A specific hydration pattern that bridges substituent and phosphate oxygen atoms in the minor groove of MOE-RNA may explain its high nuclease resistance.
  Selected figure(s)  
Figure 2.
Figure 2. Geometry and topology of the MOE-RNA duplex. a, Helical rise (black), twist (blue) and inclination (red) values for individual base pairs in the LT1 MOE-RNA duplex, calculated with the program CURVES^36. Straight lines indicate the corresponding values for standard A-form RNA. b, Stereo view of the overall conformation of the LT3 MOE-RNA dodecamer duplex and the Mg^2+ ions bound in its major groove. The Mg^2+ hexahydrate complex on the left is located on the crystallographic dyad. Atoms are colored gray, orange, red, green and blue for magnesium, phosphorus, carbon, oxygen and nitrogen, respectively. Hydrogen bonds are solid black lines and terminal residues are labeled. c, Molecular surface representation of the MOE-RNA LT2 duplex, viewed into the minor groove. Atoms of phosphate groups and MOE substituents are colored orange and green, respectively, and all others are colored light gray.
Figure 4.
Figure 4. MOE-mediated hydration of residues with gauche and trans conformations around the ethyl bond of the 2'-O-substituent. The coloring of MOE carbon atoms corresponds to the conformation around the ethyl bond and matches the color scheme of the histogram in Fig. 3b. a, Residue G22 of structure LT1, g^− conformation. b, Residue G2 of structure LT1, g^+ conformation. c, Residue G24 of structure LT3, t conformation. Atoms are colored orange, green, red and blue for phosphorus, carbon, oxygen and nitrogen, respectively. Water molecules are drawn as large cyan colored spheres and hydrogen bonds are solid black lines.
  The above figures are reprinted by permission from Macmillan Publishers Ltd: Nat Struct Biol (1999, 6, 535-539) copyright 1999.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21031200 M.Sekine, Y.Oeda, Y.Iijima, H.Taguchi, A.Ohkubo, and K.Seio (2011).
Synthesis and hybridization properties of 2'-O-methylated oligoribonucleotides incorporating 2'-O-naphthyluridines.
  Org Biomol Chem, 9, 210-218.  
20055705 C.F.Bennett, and E.E.Swayze (2010).
RNA targeting therapeutics: molecular mechanisms of antisense oligonucleotides as a therapeutic platform.
  Annu Rev Pharmacol Toxicol, 50, 259-293.  
20087997 M.Egli, and P.S.Pallan (2010).
Crystallographic studies of chemically modified nucleic acids: a backward glance.
  Chem Biodivers, 7, 60-89.  
20186448 M.M.Rodriguez-Ramos, and J.J.Wilker (2010).
Metal-bipyridine complexes in DNA backbones and effects on thermal stability.
  J Biol Inorg Chem, 15, 629-639.  
21117960 M.S.Baek, R.Z.Yu, H.Gaus, J.S.Grundy, and R.S.Geary (2010).
In vitro metabolic stabilities and metabolism of 2'-O-(methoxyethyl) partially modified phosphorothioate antisense oligonucleotides in preincubated rat or human whole liver homogenates.
  Oligonucleotides, 20, 309-316.  
19333476 P.S.Pallan, T.P.Prakash, F.Li, R.L.Eoff, M.Manoharan, and M.Egli (2009).
A conformational transition in the structure of a 2'-thiomethyl-modified DNA visualized at high resolution.
  Chem Commun (Camb), (), 2017-2019.
PDB codes: 3ey1 3ey2 3ey3
17341465 E.C.Juan, J.Kondo, T.Kurihara, T.Ito, Y.Ueno, A.Matsuda, and A.Takénaka (2007).
Crystal structures of DNA:DNA and DNA:RNA duplexes containing 5-(N-aminohexyl)carbamoyl-modified uracils reveal the basis for properties as antigene and antisense molecules.
  Nucleic Acids Res, 35, 1969-1977.
PDB codes: 2dp7 2dpb 2dpc 2dqo 2dqp 2dqq
17182632 E.E.Swayze, A.M.Siwkowski, E.V.Wancewicz, M.T.Migawa, T.K.Wyrzykiewicz, G.Hung, B.P.Monia, and C.F.Bennett (2007).
Antisense oligonucleotides containing locked nucleic acid improve potency but cause significant hepatotoxicity in animals.
  Nucleic Acids Res, 35, 687-700.  
17288535 M.Egli, and P.S.Pallan (2007).
Insights from crystallographic studies into the structural and pairing properties of nucleic acid analogs and chemically modified DNA and RNA oligonucleotides.
  Annu Rev Biophys Biomol Struct, 36, 281-305.  
16170156 B.Diop-Frimpong, T.P.Prakash, K.G.Rajeev, M.Manoharan, and M.Egli (2005).
Stabilizing contributions of sulfur-modified nucleotides: crystal structure of a DNA duplex with 2'-O-[2-(methoxy)ethyl]-2-thiothymidines.
  Nucleic Acids Res, 33, 5297-5307.
PDB code: 2axb
15788747 M.Plevnik, Z.Gdaniec, and J.Plavec (2005).
Solution structure of a modified 2',5'-linked RNA hairpin involved in an equilibrium with duplex.
  Nucleic Acids Res, 33, 1749-1759.
PDB code: 1xv6
15196747 F.Shi, and D.Hoekstra (2004).
Effective intracellular delivery of oligonucleotides in order to make sense of antisense.
  J Control Release, 97, 189-209.  
17191797 T.S.Zatsepin, Y.M.Ivanova, and T.S.Oretskaya (2004).
Synthesis of (2'S)- and (2'R)-2'-deoxy-2'-[(2-methoxyethoxy)amino] pyrimidine nucleosides and oligonucleotides.
  Chem Biodivers, 1, 1537-1545.  
12736317 E.Ennifar, P.Walter, and P.Dumas (2003).
A crystallographic study of the binding of 13 metal ions to two related RNA duplexes.
  Nucleic Acids Res, 31, 2671-2682.
PDB codes: 1nlc 1nle 1o3z 1wvd 1y6s 1y6t 1y73 1y90 1y95 2oij
12954113 L.Shen, A.Siwkowski, E.V.Wancewicz, E.Lesnik, M.Butler, D.Witchell, G.Vasquez, B.Ross, O.Acevedo, G.Inamati, H.Sasmor, M.Manoharan, and B.P.Monia (2003).
Evaluation of C-5 propynyl pyrimidine-containing oligonucleotides in vitro and in vivo.
  Antisense Nucleic Acid Drug Dev, 13, 129-142.  
12682357 M.Polak, M.Manoharan, G.B.Inamati, and J.Plavec (2003).
Tuning of conformational preorganization in model 2',5'- and 3',5'-linked oligonucleotides by 3'- and 2'-O-methoxyethyl modification.
  Nucleic Acids Res, 31, 2066-2076.  
12466541 A.Tsourkas, M.A.Behlke, and G.Bao (2002).
Hybridization of 2'-O-methyl and 2'-deoxy molecular beacons to RNA and DNA targets.
  Nucleic Acids Res, 30, 5168-5174.  
12491456 C.J.Wilds, M.A.Maier, V.Tereshko, M.Manoharan, and M.Egli (2002).
Direct observation of a cytosine analogue that forms five hydrogen bonds to guanosine: guanidino G-clamp.
  Angew Chem Int Ed Engl, 41, 115-117.
PDB code: 1kgk
11876654 C.N.Lok, E.Viazovkina, K.L.Min, E.Nagy, C.J.Wilds, M.J.Damha, and M.A.Parniak (2002).
Potent gene-specific inhibitory properties of mixed-backbone antisense oligonucleotides comprised of 2'-deoxy-2'-fluoro-D-arabinose and 2'-deoxyribose nucleotides.
  Biochemistry, 41, 3457-3467.  
12074364 M.Manoharan (2002).
Oligonucleotide conjugates as potential antisense drugs with improved uptake, biodistribution, targeted delivery, and mechanism of action.
  Antisense Nucleic Acid Drug Dev, 12, 103-128.  
12465035 M.Manoharan, G.B.Inamati, E.A.Lesnik, N.B.Sioufi, and S.M.Freier (2002).
Improving antisense oligonucleotide binding to human serum albumin: dramatic effect of ibuprofen conjugation.
  Chembiochem, 3, 1257-1260.  
11353086 A.Sabahi, J.Guidry, G.B.Inamati, M.Manoharan, and P.Wittung-Stafshede (2001).
Hybridization of 2'-ribose modified mixed-sequence oligonucleotides: thermodynamic and kinetic studies.
  Nucleic Acids Res, 29, 2163-2170.  
11600703 D.A.Adamiak, W.R.Rypniewski, J.Milecki, and R.W.Adamiak (2001).
The 1.19 A X-ray structure of 2'-O-Me(CGCGCG)(2) duplex shows dehydrated RNA with 2-methyl-2,4-pentanediol in the minor groove.
  Nucleic Acids Res, 29, 4144-4153.
PDB code: 1i7j
11222771 V.Tereshko, C.J.Wilds, G.Minasov, T.P.Prakash, M.A.Maier, A.Howard, Z.Wawrzak, M.Manoharan, and M.Egli (2001).
Detection of alkali metal ions in DNA crystals using state-of-the-art X-ray diffraction experiments.
  Nucleic Acids Res, 29, 1208-1215.
PDB codes: 1i0f 1i0g 1i0j 1i0k 1i0m 1i0n 1i0o 1i0p 1i0q 1i0t
10982885 C.J.Wilds, and M.J.Damha (2000).
2'-Deoxy-2'-fluoro-beta-D-arabinonucleosides and oligonucleotides (2'F-ANA): synthesis and physicochemical studies.
  Nucleic Acids Res, 28, 3625-3635.  
10736151 G.Minasov, M.Teplova, P.Nielsen, J.Wengel, and M.Egli (2000).
Structural basis of cleavage by RNase H of hybrids of arabinonucleic acids and RNA.
  Biochemistry, 39, 3525-3532.
PDB code: 1ei4
10807002 M.Manoharan (1999).
2'-carbohydrate modifications in antisense oligonucleotide therapy: importance of conformation, configuration and conjugation.
  Biochim Biophys Acta, 1489, 117-130.  
10588690 M.Teplova, S.T.Wallace, V.Tereshko, G.Minasov, A.M.Symons, P.D.Cook, M.Manoharan, and M.Egli (1999).
Structural origins of the exonuclease resistance of a zwitterionic RNA.
  Proc Natl Acad Sci U S A, 96, 14240-14245.
PDB codes: 1d8y 1d9d 1d9f 1d9h
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.