PDBsum entry 468d

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Waters ×111

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Title Crystal structure and improved antisense properties of 2'-O-(2-Methoxyethyl)-Rna.
Authors M.Teplova, G.Minasov, V.Tereshko, G.B.Inamati, P.D.Cook, M.Manoharan, M.Egli.
Ref. Nat Struct Biol, 1999, 6, 535-539. [DOI no: 10.1038/9304]
PubMed id 10360355
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.
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.