The effects of local DNA sequence on the interaction of ligands with their preferred binding sites

Hampshire, Andrew J.; Fox, Keith R.

doi:10.1016/j.biochi.2008.01.001

Cited by 38 publications

(31 citation statements)

References 65 publications

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“…Binding to a GC sequence is strengthened by flanking TA steps, and a GC site is preferred over a CG site [24,28,30]. DNase I footprinting using DNA fragments containing all 64 symmetrical hexanucleotide sequences demonstrated that MTM binds best to AGCGCT and GGGCCC [29]. However, this study also showed that MTM also bound well at non-GC sites, such as ACCGGT.…”

Section: Introductionmentioning

confidence: 96%

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Dimerization and DNA recognition rules of mithramycin and its analogues

Weidenbach

Hou

Chen

et al. 2016

Journal of Inorganic Biochemistry

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The antineoplastic and antibiotic natural product mithramycin (MTM) is used against cancer-related hypercalcemia and, experimentally, against Ewing sarcoma and lung cancers. MTM exerts its cytotoxic effect by binding DNA as a divalent metal ion (Me2+)-coordinated dimer and disrupting the function of transcription factors. A precise molecular mechanism of action of MTM, needed to develop MTM analogues selective against desired transcription factors, is lacking. Although it is known that MTM binds G/C-rich DNA, the exact DNA recognition rules that would allow one to map MTM binding sites remain incompletely understood. Towards this goal, we quantitatively investigated dimerization of MTM and several of its analogues, MTM SDK (for Short side chain, DiKeto), MTM SA-Trp (for Short side chain and Acid), MTM SA-Ala, and a biosynthetic precursor premithramycin B (PreMTM B), and measured the binding affinities of these molecules to DNA oligomers of different sequences and structural forms at physiological salt concentrations. We show that MTM and its analogues form stable dimers even in the absence of DNA. All molecules, except for PreMTM B, can bind DNA with the following rank order of affinities (strong to weak): MTM = MTM SDK > MTM SA-Trp > MTM SA-Ala. An X(G/C)(G/C)X motif, where X is any base, is necessary and sufficient for MTM binding to DNA, without a strong dependence on DNA conformation. These recognition rules will aid in mapping MTM sites across different promoters towards development of MTM analogues as useful anticancer agents.

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Section: Introductionmentioning

confidence: 96%

“…For example, whether MTM recognizes a specific DNA sequence (direct readout), DNA conformation (indirect readout) or both, is not clear [26]. MTM preferentially binds G/C-rich sequences [24,27–29]. Binding to a GC sequence is strengthened by flanking TA steps, and a GC site is preferred over a CG site [24,28,30].…”

Section: Introductionmentioning

confidence: 99%

Dimerization and DNA recognition rules of mithramycin and its analogues

Weidenbach

Hou

Chen

et al. 2016

Journal of Inorganic Biochemistry

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“…Many of these compounds exhibit a preference for binding to AT sequences of at least four consecutive AT base pairs in the binding site (1–8,19,22). A number of X-ray crystallographic structures have been obtained with compounds bound to the minor groove of a four base pair AATT sequence in a self-complementary duplex, d(CGCGAATTCGCG) 2 (19,23).…”

Section: Introductionmentioning

confidence: 99%

Complexity in the binding of minor groove agents: netropsin has two thermodynamically different DNA binding modes at a single site

Lewis

Munde

Wang

et al. 2011

Nucleic Acids Research

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Structural results with minor groove binding agents, such as netropsin, have provided detailed, atomic level views of DNA molecular recognition. Solution studies, however, indicate that there is complexity in the binding of minor groove agents to a single site. Netropsin, for example, has two DNA binding enthalpies in isothermal titration calorimetry (ITC) experiments that indicate the compound simultaneously forms two thermodynamically different complexes at a single AATT site. Two proposals for the origin of this unusual observation have been developed: (i) two different bound species of netropsin at single binding sites and (ii) a netropsin induced DNA hairpin to duplex transition. To develop a better understanding of DNA recognition complexity, the two proposals have been tested with several DNAs and the methods of mass spectrometry (MS), polyacrylamide gel electrophoresis (PAGE) and nuclear magnetic resonance spectroscopy in addition to ITC. All of the methods with all of the DNAs investigated clearly shows that netropsin forms two different complexes at AATT sites, and that the proposal for an induced hairpin to duplex transition in this system is incorrect.

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“…In order to understand the effect of local sequence on ligand binding, it is necessary to explore a range of potential binding sites in a series of different contexts [14]. In the present study, the effect of FLX binding to poly (A-T) and poly (C-G) were tested and the results were analyzed.…”

Section: Effects Of Dna Sequence On the Interaction With Flxmentioning

confidence: 99%

“…Moreover in the past 30 years many small molecules have been discovered that bind to DNA in a sequence selective fashion. It is clear that the interaction of ligands with their DNA target sites can be modulated by the local sequence context, largely due to sequence dependent changes in the local structure and/or dynamics [14].…”

Section: Introductionmentioning

confidence: 99%