title: A regular thymine tetrad and a peculiar supramolecular assembly in the first crystal structure of an all-LNA G-quadruplex.
abstract: 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 Å 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.
authors: Department of Chemical Sciences, University of Naples `Federico II', Complesso Universitario di Monte Sant'Angelo, Via Cinthia, I-80126 Napoli, Italy.
authors: Irene
authors: I
authors: Russo Krauss
authors: Department of Pharmaceutical and Biological Chemistry, UCL School of Pharmacy, University College London, 29-39 Brunswick Square, London WC1N 1AX, England.
authors: Gary Nigel
authors: GN
authors: Parkinson
authors: Department of Chemical Sciences, University of Naples `Federico II', Complesso Universitario di Monte Sant'Angelo, Via Cinthia, I-80126 Napoli, Italy.
authors: Antonello
authors: A
authors: Merlino
authors: Department of Pharmacy, University of Salerno, Via Ponte Don Melillo, I-84084 Fisciano, Italy.
authors: Carlo Andrea
authors: CA
authors: Mattia
authors: Department of Pharmacy, University of Naples `Federico II', Via D. Montesano 49, I-80131 Napoli, Italy.
authors: Antonio
authors: A
authors: Randazzo
authors: Department of Pharmacy, University of Naples `Federico II', Via D. Montesano 49, I-80131 Napoli, Italy.
authors: Ettore
authors: E
authors: Novellino
authors: Department of Chemical Sciences, University of Naples `Federico II', Complesso Universitario di Monte Sant'Angelo, Via Cinthia, I-80126 Napoli, Italy.
authors: Lelio
authors: L
authors: Mazzarella
authors: Department of Chemical Sciences, University of Naples `Federico II', Complesso Universitario di Monte Sant'Angelo, Via Cinthia, I-80126 Napoli, Italy.
authors: Filomena
authors: F
authors: Sica
mesh_terms: D018360:Crystallography, X-Ray; D054856:G-Quadruplexes; D008958:Models, Molecular; D009841:Oligonucleotides / Q000737:chemistry*; D013816:Thermodynamics; D013941:Thymine / Q000737:chemistry*
chemical_list: D009841:Oligonucleotides; C477371:locked nucleic acid; D013941:Thymine
keywords: G-quadruplex; locked nucleic acids; thymine tetrad