Details

Autor(en) / Beteiligte

• Laughlin, Sarah
• Wang, Siming
• Kumar, Arvind
• Farahat, Abdelbasset A.
• Boykin, David W.
• Wilson, W. David

Titel

Resolution of Mixed Site DNA Complexes with Dimer-Forming Minor-Groove Binders by Using Electrospray Ionization Mass Spectrometry: Compound Structure and DNA Sequence Effects

Ist Teil von

• Chemistry : a European journal, 2015-03, Vol.21 (14), p.5528-5539

Ort / Verlag

Weinheim: WILEY-VCH Verlag

Erscheinungsjahr

2015

Link zum Volltext

Quelle

Wiley Blackwell Single Titles

Beschreibungen/Notizen

• Small‐molecule targeting of the DNA minor groove is a promising approach to modulate genomic processes necessary for normal cellular function. For instance, dicationic diamindines, a well‐known class of minor groove binding compounds, have been shown to inhibit interactions of transcription factors binding to genomic DNA. The applications of these compounds could be significantly expanded if we understand sequence‐specific recognition of DNA better and could use the information to design more sequence‐specific compounds. Aside from polyamides, minor groove binders typically recognize DNA at A‐tract or alternating AT base pair sites. Targeting sites with GC base pairs, referred to here as mixed base pair sequences, is much more difficult than those rich in AT base pairs. Compound 1 is the first dicationic diamidine reported to recognize a mixed base pair site. It binds in the minor groove of ATGA sequences as a dimer with positive cooperativity. Due to the well‐characterized behavior of 1 with ATGA and AT rich sequences, it provides a paradigm for understanding the elements that are key for recognition of mixed sequence sites. Electrospray ionization mass spectrometry (ESI‐MS) is a powerful method to screen DNA complexes formed by analogues of 1 for specific recognition. We also report a novel approach to determine patterns of recognition by 1 for cognate ATGA and ATGA‐mutant sequences. We found that functional group modifications and mutating the DNA target site significantly affect binding and stacking, respectively. Both compound conformation and DNA sequence directionality are crucial for recognition. Dimer system in DNA minor groove: A developed competitive ESI mass spectrometry method was used in the discovery of a new binding mode by a synthetic minor groove binding compound. The compound recognizes mixed DNA base pair sites as a cooperative dimer complex through stacking as an antiparallel system within the minor groove of mixed base pair sequences (see figure).