A regular thymine tetrad and a peculiar supramolecular assembly in the first crystal structure of an all-LNA G-quadruplex(610 views) Russo Krauss I, Parkinson GN, Merlino A, Mattia CA, Randazzo A, Novellino E, Mazzarella L, Sica F
Keywords: G-Quadruplex, Locked Nucleic Acids, Thymine Tetrad, Guanine Quadruplex, Oligonucleotide, Article, Chemical Structure, Chemistry, Thermodynamics, X Ray Crystallography, X-Ray, Models, Molecular,
Affiliations: *** IBB - CNR ***
Department of Chemical Sciences, University of Naples 'Federico II', Complesso Universitario di Monte sant'Angelo, Via Cinthia, I-80126 Napoli, Italy
Department of Pharmaceutical and Biological Chemistry, UCL School of Pharmacy, University College London, 29-39 Brunswick Square, London WC1N 1AX, United Kingdom
Institute of Biostructure and Bioimages, CNR, Via Mezzocannone 16, I-80134 Napoli, Italy
National Institute Biostructures and Biosystems, Inter-University Consortium, Viale Medaglie d'Oro 305, I-00136 Rome, Italy
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A regular thymine tetrad and a peculiar supramolecular assembly in 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. They represent a promising tool for therapeutic and diagnostic applications and are characterized by higher thermal stability and nuclease resistance with respect to their natural counterparts. However, structural descriptions of LNA-containing quadruplexes are rather limited, since few NMR models have been reported in the literature. Here, the first crystallographically derived model of an all-LNA-substituted quadruplex-forming sequence 5'-TGGGT-3' is presented refined at 1.7 angstrom resolution. This high-resolution crystallographic analysis reveals a regular parallel G-quadruplex arrangement terminating in a well defined thymine tetrad at the 3'-end. The detailed picture of the hydration pattern reveals LNA-specific features in the solvent distribution. Interestingly, two closely packed quadruplexes are present in the asymmetric unit. They face one another with their 3'-ends giving rise to a compact higher-order structure. This new assembly suggests a possible way in which sequential quadruplexes can be disposed in the crowded cell environment. Furthermore, as the formation of ordered structures by molecular self-assembly is an effective strategy to obtain nanostructures, this study could open the way to the design of a new class of LNA-based building blocks for nanotechnology.
A regular thymine tetrad and a peculiar supramolecular assembly in the first crystal structure of an all-LNA G-quadruplex