The First Crystal Structure of an All LNA G-Quadruplex

Locked nucleic acids (LNAs) are formed by bicyclic ribonucleotides where the O2’ and C4’ atoms are linked through a methylene bridge and the sugar is blocked in a 3’-endo conformation [1]. They represent a promising tool for therapeutic and diagnostic applications, characterized by higher thermal stability and nucleases resistance with respect to their natural counterparts [2,3]. However, structural descriptions of LNA-containing quadruplexes are rather limited, and up to now no crystal structure was reported. Here we present the first crystallographically derived model of an all LNA-substituted quadruplex forming sequence 5’-TGGGT-3’. The presence of two closely packed quadruplexes in the asymmetric unit made structural determination particularly changeling, but eventually a very good model at 1.7 Å resolution has been obtained. Structural details derived from this first high resolution crystallographic model of an all-LNA quadruplex add important information to our knowledge of the effect of modified nucleotides in quadruplex structure and stability. Moreover, the unusual stacked arrangement of the two quadruplexes in the asymmetric unit suggests how sequential quadruplexes can arrange in the crowded cell environment, while at the same time the structure provides an opportunity in the design of LNA-based blocks for developing scaffolds within nanotechnology applications. [1] S.K. Singh, P. Nielsen, A.A. Koshkin, J. Wengel Chem Commun, 1998, 455-456. [2] H. Doessing, B. Vester Molecules, 2011,16, 4511-4526. [3] H. Kaur, B.R. Babu, S. Maiti Chemical reviews, 2007,107, 4672-4697.