Journal
JOURNAL OF MOLECULAR BIOLOGY
Volume 381, Issue 5, Pages 1145-1156Publisher
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jmb.2008.06.022
Keywords
quadruplex; ligand interaction; telomeric DNA; X-ray structures; topology
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Funding
- Cancer Research UK [C129/A489]
- European Union [LSHC-CT-2004-502943]
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Knowledge of the biologically relevant topology is critical for the design of drugs targeting quadruplex nucleic acids. We report here crystal structures of a G-quadruplex-selective ligand complexed with two human telomeric DNA quadruplexes. The intramolecular quadruplex sequence d[TAGGG (TTAGGG)(3)] and the bimolecular quadruplex sequence d(TAGGGT-TAGGGT) were co-crystallized with a tetra-substituted naphthalene diimide quadruplex-binding ligand. The structures were solved and refined to 2.10- and 2.20-angstrom resolution, respectively, revealing that the quadruplex topology in both structures is unchanged by the addition of the ligands, retaining a parallel-stranded arrangement with external double-chain-reversal propeller loops. The parallel topology results in accessible external 5' and 3' planar G-tetrad surfaces for ligand stacking. This also enables significant ligand-induced conformational changes in several TTA propeller loops to take place such that the loops themselves are able to accommodate bound drug molecules without affecting the parallel quadruplex topology, by stacking on the external TTA connecting loop nucleotides. Ligands are bound into the external TTA loop nucleotides and stack onto G-tetrad surfaces. These crystal structures provide a framework for further ligand development of the naphthalene diimide series to enhance selectivity and affinity. (c) 2008 Elsevier Ltd. All rights reserved.
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