Angewandte Chemie - International Edition
Angewandte Chemie - International Edition
5 years ago

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

Solution NMR Structure of a Ligand/Hybrid-2-G-Quadruplex Complex Reveals Rearrangements that Affect Ligand Binding
Luigi Messori, Lars Erik Bendel, J. Tassilo Grün, Francesco Papi, Hendrik R. A. Jonker, Carla Bazzicalupi, Harald Schwalbe, Paola Gratteri, Julia Wirmer-Bartoschek
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. Conformation matters: G-quadruplexes are emerging drug targets in cancer research. The first NMR structure determination of a telomeric DNA G-quadruplex in the hybrid-2 conformation in complex with a ligand is reported. The structure reveals major changes in the capping regions of the G-quadruplex, highlighting the importance of obtaining a ligand-bound structure to aid rational drug design.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1002/anie.201702135

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