Intercalation of a Heterocyclic Ligand between Quartets in a G-Rich Tetrahelical Structure |
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Authors: | Dr Anita Kotar Dr Vojč Kocman Prof Dr Janez Plavec |
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Institution: | 1. National Institute of Chemistry, Hajdrihova 19, 1000 Ljubljana, Slovenia
These authors contributed equally to this work.;2. National Institute of Chemistry, Hajdrihova 19, 1000 Ljubljana, Slovenia |
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Abstract: | YES G-rich oligonucleotide VK2 folds into an AGCGA-quadruplex tetrahelical structure distinct and significantly different from G-quadruplexes, even though it contains four G3 tracts. Herein, a bis-quinolinium ligand 360A with high affinity for G-quadruplex structures and selective telomerase inhibition is shown to strongly bind to VK2. Upon binding, 360A does not induce a conformational switch from VK2 to an expected G-quadruplex. In contrast, NMR structural study revealed formation of a well-defined VK2–360A complex with a 1:1 binding stoichiometry, in which 360A intercalates between GAGA- and GCGC-quartets in the central cavity of VK2. This is the first high-resolution structure of a G-quadruplex ligand intercalating into a G-rich tetrahelical fold. This unique mode of ligand binding into tetrahelical DNA architecture offers insights into the stabilization of an AGCGA-quadruplex by a heterocyclic ligand and provides guidelines for rational design of novel VK2 binding molecules with selectivity for different DNA secondary structures. |
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Keywords: | 360A complex AGCGA-quadruplex G-quadruplex G-rich regions NMR |
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