First look at RNA in L-configuration

Nucleic acid molecules in the mirror image or L-configuration are unknown in nature and are extraordinarily resistant to biological degradation. The identification of functional L-­oligonucleotides called Spiegelmers offers a novel approach for drug discovery based on RNA. The sequence r(CUGGGCGG)·r(CCGCCUGG) was chosen as a model system for structural analysis of helices in the L-configuration as the structure of the D-form of this sequence has previously been determined in structural studies of 5S RNA domains, in particular domain E of the Thermus flavus 5S rRNA [Perbandt et al. (2001), Acta Cryst. D57, 219-224]. Unexpectedly, the results of crystallization trials showed little similarity between the D- and the L-forms of the duplex in either the crystallization hits or the diffraction performance. The crystal structure of this L-RNA duplex has been determined at 1.9 Å resolution with R_work and R_free of 23.8 and 28.6%, respectively. The crystals belong to space group R32, with unit-cell parameters a = 45.7, c = 264.6 Å. Although there are two molecules in the asymmetric unit rather than one, the structure of the L-form arranges helical pairs in a head-to-tail fashion to form pseudo-continuous infinite helices in the crystal as in the D-form. On the other hand, the wobble-like G·C⁺ base pair seen in the D-RNA analogue does not appear in the L-RNA duplex, which forms a regular double-helical structure with typical Watson-Crick base pairing.