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Entropically-driven binding of mithramycin in the minor groove of C/G-rich DNA sequences

AuthorsBarceló, Francisca; Scotta, Claudia; Ortiz-Lombardía, Miguel; Méndez, Carmen; Salas, José A.; Portugal, José
Issue Date16-Mar-2007
PublisherOxford University Press
CitationNucleic Acids Res. 2007 April; 35(7): 2215–2226.
AbstractThe antitumour antibiotic mithramycin A (MTA) is a DNA minor-groove binding ligand. It binds to C/G-rich tracts as a dimer that forms in the presence of divalent cations such as Mg2+. Differential scanning calorimetry, UV thermal denaturation, isothermal titration calorimetry and competition dialysis were used, together with computations of the hydrophobic free energy of binding, to determine the thermodynamic profile of MTA binding to DNA. The results were compared to those obtained in parallel using the structurally related mithramycin SK (MSK). The binding of MTA to salmon testes DNA determined by UV melting studies (Kobs = 1.2 (±0.3) x 10^5 M–1) is tighter than that of MSK (2.9 (±1.0) x 10^4 M–1) at 25°C. Competition dialysis studies showed a tighter MTA binding to both salmon testes DNA (42% C + G) and Micrococcus lysodeikticus DNA (72% C + G). The thermodynamic analysis of binding data at 25°C shows that the binding of MTA and MSK to DNA is entropically driven, dominated by the hydrophobic transfer of the antibiotics from solution to the DNA-binding site. Direct molecular recognition between MTA or MSK and DNA through hydrogen bonding and van der Waals contacts may also contribute significantly to complex formation.
DescriptionFinal full-text version available at: http://dx.doi.org/10.1093/nar/gkm037.-- Supplementary Data is available.
Publisher version (URL)http://dx.doi.org/10.1093/nar/gkm037
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