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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.

Author information

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; G-quadruplexes; NMR spectroscopy; drug design; structure elucidation

PMID:
28524432
DOI:
10.1002/anie.201702135
[Indexed for MEDLINE]

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