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Solution NMR Structure of a Ligand/Hybrid-2-G-Quadruplex Complex Reveals Rearrangements that Affect Ligand Binding |
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| Authors: | Dr Julia Wirmer-Bartoschek Lars Erik Bendel Dr Hendrik R A Jonker J Tassilo Grün Dr Francesco Papi Prof Dr Carla Bazzicalupi Prof Dr Luigi Messori Prof Dr Paola Gratteri Prof Dr Harald Schwalbe |
| Institution: | 1. Institute for Organic Chemistry and Chemical Biology, Center of Biomolecular Magnetic Resonance (BMRZ), Goethe University Frankfurt/Main, Max-von-Laue-Strasse 7, 60439 Frankfurt, Germany;2. Dipartimento di Chimica “Ugo Schiff”, Università degli Studi di Firenze, Via della Lastruccia 3, 50019 Sesto Fiorentino (FI), Italy;3. Dipartimento di Neuroscienze, Psicologia, Area del Farmaco, Salute del Bambino (NEUROFARBA), Università degli Studi di Firenze, via Ugo Schiff 6, 50019 Sesto Fiorentino, Italy |
| Abstract: | Telomeric G-quadruplexes have recently emerged as drug targets in cancer research. Herein, we present the first NMR structure of a telomeric DNA G-quadruplex that adopts the biologically relevant hybrid-2 conformation in a ligand-bound state. We solved the complex with a metalorganic gold(III) ligand that stabilizes G-quadruplexes. Analysis of the free and bound structures reveals structural changes in the capping region of the G-quadruplex. The ligand is sandwiched between one terminal G-tetrad and a flanking nucleotide. This complex structure involves a major structural rearrangement compared to the free G-quadruplex structure as observed for other G-quadruplexes in different conformations, invalidating simple docking approaches to ligand–G-quadruplex structure determination. |
| Keywords: | DNA–ligand complexes drug design G-quadruplexes NMR spectroscopy structure elucidation |