NMR Studies of G-Quadruplex Structures and G-Quadruplex-Interactive Compounds
G-quadruplexes are noncanonical, four-stranded nucleic acid secondary structures formed in sequences containing consecutive runs of guanines. These G-quadruplex structures have been found to form in nucleic acid regions of biological significance, includi
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Introduction G-quadruplexes are noncanonical, four-stranded nucleic acid secondary structures formed in sequences containing consecutive runs of guanines, which have recently emerged as attractive cancer therapeutic targets [1]. They are built from stacked G-tetrad planes, consisting of four guanine bases connected by a square network of Hoogsteen hydrogen bonding (Fig. 1a). G-quadruplexes can be formed with one, two, or four G-rich nucleic acid molecules (Fig. 1b). Within a G-quadruplex structure, G-strands can be parallel or antiparallel, and G-tetrad guanines can adopt anti or syn conformations around the glycosidic bonds. G-tetrad guanines from parallel G-strands adopt the same glycosidic conformation while those from antiparallel G-strands adopt the opposite glycosidic conformation (Fig. 1c). Formation of G-quadruplex structures requires the presence of monovalent cations, such as K+ and Na+, to coordinate with the eight electronegative O6 atoms of the adjacent stacked G-tetrads [2] (Fig. 1a). K+ is preferred over Na+ by G-quadruplexes in general for its better coordination with the
Danzhou Yang and Clement Lin (eds.), G-Quadruplex Nucleic Acids: Methods and Protocols, Methods in Molecular Biology, vol. 2035, https://doi.org/10.1007/978-1-4939-9666-7_9, © Springer Science+Business Media, LLC, part of Springer Nature 2019
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Fig. 1 (a) Schematic diagram of a G-tetrad containing a square planar alignment of four guanines connected by cyclic Hoogsteen hydrogen bonding between the N1, N2 and O6, N7 of guanine bases. Curved lines show the H1-H1 and H1-H8 connectivity pattern detectable in NOESY experiments. (b) Schematic diagrams of monomeric (intramolecular), dimeric, and tetrameric G-quadruplexes. (c) The guanines in a G-tetrad can adopt either syn or anti glycosidic conformation depending on the orientation of DNA strands
guanine O6s and lower dehydration energy [3]. Due to their potential formation in biologically relevant regions [1, 4–7], intramolecular G-quadruplexes are a subject of significant research interest. These intramolecular G-quadruplex structures form quickly in solution and are found to be DNA sequence-specific, exhibiting great conformational diversity, such as in folding topologies, loop conformations, and capping structures [1]. Recognition of the biological significance of G-quadruplexes has intensified research and development of G-quadruplex interactive compounds. Targeting of G-quadruplex secondary structures in DNA represents a new approach for cancer therapeutics [1, 7–10], with the first report of targeting G-quadruplexes for inhibiting telomerase activity in 1997 [11]. Formation of diverse G-quadruplex structures offers an opportunity to design small molecules/ligands that can selectively bind different G-quadruplexes. Structure-based drug design has been playing an i
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