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Angew Chem Int Ed Engl. 2017 Jun 12;56(25):7102-7106. doi: 10.1002/anie.201702135. Epub 2017 May 19.

Solution NMR Structure of a Ligand/Hybrid-2-G-Quadruplex Complex Reveals Rearrangements that Affect Ligand Binding.

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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.
Dipartimento di Chimica "Ugo Schiff", Università degli Studi di Firenze, Via della Lastruccia 3, 50019, Sesto Fiorentino (FI), Italy.
Dipartimento di Neuroscienze, Psicologia, Area del Farmaco, Salute del Bambino (NEUROFARBA), Università degli Studi di Firenze, via Ugo Schiff 6, 50019, Sesto Fiorentino, Italy.


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.


DNA-ligand complexes; G-quadruplexes; NMR spectroscopy; drug design; structure elucidation

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