Nucleic Acids Research Advance Access originally published online on March 16, 2007
Nucleic Acids Research 2007 35(7):2215-2226; doi:10.1093/nar/gkm037
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Nucleic Acids Research, 2007, Vol. 35, No. 7 2215-2226
© 2007 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Structural Biology |
Entropically-driven binding of mithramycin in the minor groove of C/G-rich DNA sequences
1Departament de Biologia Fundamental i Ciencies de la Salut, Universitat de les Illes Balears, Palma de Mallorca, Spain, 2Programa de Biologia Estructural y Biocomputacion, Centro Nacional de Investigaciones Oncologicas (CNIO), Madrid, Spain, 3Departamento de Biologia Funcional-Instituto Universitario de Oncologia del Principado de Asturias, Oviedo, Spain and 4Instituto de Biologia Molecular de Barcelona, CSIC, Parc Cientific de Barcelona, Barcelona, Spain
*To whom correspondence should be addressed. Tel: +34 93 403 4959; Fax: +34 93 403 4979; Email: jpmbmc{at}ibmb.csic.es
Received October 31, 2006. Revised December 14, 2006. Accepted January 8, 2007.
The 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 105 M–1) is tighter than that of MSK (2.9 (±1.0) x 104 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.
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