Title
Selective Targeting of G-Quadruplex Structures by a Benzothiazole-Based Binding Motif
Author
Ina Buchholz, Beatrice Karg, Jonathan Dickerhoff, Adrian Sievers-Engler, Michael Lämmerhofer, Klaus Weisz
Year
2017
Journal
Chemistry A European Journal
Abstract
A benzothiazole derivative was identified as potent ligand for DNA G-quadruplex structures. Fluorescence titrations revealed selective binding to quadruplexes of different topologies including parallel, antiparallel and (3+1) hybrid structures. The parallel c-MYC sequence was found to constitute the preferred target with dissociation constants in the micromolar range. Binding of the benzothiazole-based ligand to c-MYC was structurally and thermodynamically characterized in detail by employing a comprehensive set of spectroscopic and calorimetric techniques. Job plot analyses and mass spectral data indicate non-cooperative ligand binding to form 1:1 and 2:1 complex stoichiometries. Whereas stacking interactions are suggested by optical methods, NMR chemical shift perturbations also indicate significant rearrangements of both 5'- and 3'-flanking sequences upon ligand binding. Additional isothermal calorimetry studies yield a thermodynamic profile of the ligand-quadruplex association and reveal enthalpic contributions to be the major driving force for binding. The structural and thermodynamic information obtained in the present work provides the basis for the rational development of benzothiazole derivatives as promising quadruplex binding agents.
Instrument
J-810
Keywords
Circular dichroism, Induced CD, DNA structure, Ligand binding, Biochemistry