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 (Singh, S.K. et al., Chem Commun, 1998, 455-6). They represent a promising tool for therapeutic and diagnostic applications, characterized by higher thermal stability and nucleases resistance with respect to their natural counterparts (Doessing, H. and Vester, B., Molecules, 2011, 16, 4511-26; Kaur, H. et al., Chemical reviews, 2007, 107, 4672-97). 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???. 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. In particular, we observe a regular terminal thymine-tetrad, the first to be observed in crystallographic structure of G-quadruplexes and a likely contributor to the high thermal stability of this molecule. 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.
The first crystal structure of an all LNA G-quadruplex: a compact moiety with potential application in nanotechnology / RUSSO KRAUSS, Irene; G., Parkinson; Merlino, Antonello; C. A., Mattia; Randazzo, Antonio; Novellino, Ettore; Mazzarella, Lelio; Sica, Filomena. - (2013). (Intervento presentato al convegno IV International Meeting on G-quadruplex Nucleic Acids from Structure to Chemistry and Biology tenutosi a Nanyang Executive Center, Nanyang Technological University, Singapore nel 1-4 Luglio 2013).
The first crystal structure of an all LNA G-quadruplex: a compact moiety with potential application in nanotechnology
RUSSO KRAUSS, IRENE;MERLINO, ANTONELLO;RANDAZZO, ANTONIO;NOVELLINO, ETTORE;MAZZARELLA, LELIO;SICA, FILOMENA
2013
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 (Singh, S.K. et al., Chem Commun, 1998, 455-6). They represent a promising tool for therapeutic and diagnostic applications, characterized by higher thermal stability and nucleases resistance with respect to their natural counterparts (Doessing, H. and Vester, B., Molecules, 2011, 16, 4511-26; Kaur, H. et al., Chemical reviews, 2007, 107, 4672-97). 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???. 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. In particular, we observe a regular terminal thymine-tetrad, the first to be observed in crystallographic structure of G-quadruplexes and a likely contributor to the high thermal stability of this molecule. 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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
