Binding to DNA

Since many metal complexes bind to DNA, those that show luminescence in fluid media have the potential to act as probes of biological structure. Such a feature is particularly useful if the luminescent probe is site specific on the DNA chain. Complexes that can be chemically modified at the ligand periphery, or whose photophysical properties are sensitive to medium effects, have the best potential for use in biological applications. 

Different types of DNA have been used to probe the binding interactions of copper(I) complexes. Luminescence data obtained from this study indicate that a guanine-cytosine base pair is sufficient to define an intercalation site.  

Metcalfe, C. and Thomas, J. A., Kinetically inert transition metal complexes that reversibly hind to DNA , Chem. Soc. Rev. 2003, 32, 215-224. 

Two of the most important platinum anticancer drugs are cisplatin (2.13) and carboplatin (2.14). Cisplatin is effective against testicular tumours, ovarian carcinoma and some other types of cancer, but relatively inactive against breast and lung cancers it is also a very toxic compound. Side effects include loss of high-frequency hearing, neuropathy and nausea. Kidney damage may also result, but is minimised 

---

This model of Cro binding to DNA was arrived at by intuition and clever model building. Its validity was considerably strengthened when the same features were subsequently found in the DNA-binding domains of the lambda-repressor molecule. The helix-turn-helix motif with a recognition helix is present in the repressor, and moreover the repressor DNA-binding domains dimerize in the crystals in such a way that the recognition helices are separated by 34 A as in Cro. 

The sharp bend of DNA at the TATA box induced by TBP binding is favorable for the formation of the complete DNA control module in particular, for the interaction of specific transcription factors with TFIID. Since these factors may bind to DNA several hundred base pairs away from the TATA box, and at the same time may interact with TBP through one or several TAFs, there must be several protein-DNA interactions within this module that distort the regular B-DNA structure (see Figure 9.2). The DNA bend caused by the binding of TBP to the TATA box is one important step to bring activators near to the site of action of RNA polymerase. 

Monomers of homeodomain proteins bind to DNA through a helix-turn-helix motif... 

The homeodomain frequently binds to DNA as a monomer, in contrast to procaryotic DNA-binding proteins containing tbe belix-turn-helix motif, which usually bind as dimers. In vitro tbe homeodomain binds specifically to... 

Figure 9.12 Schematic diagram of the structure of the heterodimeric yeast transcription factor Mat a2-Mat al bound to DNA. Both Mat o2 and Mat al are homeodomains containing the helix-turn-helix motif. The first helix in this motif is colored blue and the second, the recognition helix, is red. (a) The assumed structure of the Mat al homeodomain in the absence of DNA, based on Its sequence similarity to other homeodomains of known structure, (b) The structure of the Mat o2 homeodomain. The C-terminal tail (dotted) is flexible in the monomer and has no defined structure, (c) The structure of the Mat a 1-Mat a2-DNA complex. The C-terminal domain of Mat a2 (yellow) folds into an a helix (4) in the complex and interacts with the first two helices of Mat a2, to form a heterodimer that binds to DNA. (Adapted from B.J. Andrews and M.S. Donoviel, Science 270 251-253, 1995.)...

Figure 9.13 The DNA-binding region of the protein Oct-1, the POU region (green), comprises two domains, the POU-specific domain (dark green) and the POU homeodomain (light green) joined by a linker region (blue). These two domains bind to DNA in a tandem arrangement.

POU regions bind to DNA by two tandemly oriented helix-turn-helix motifs... 

Figure 9.14 The two domains of the POU region bind in tandem on opposite sides of the DNA double helix. Both the POU-specific domain and the POU homeodomain have a helix-turn-helix motif (blue and red) which binds to DNA with their recognition helices (red) in the major groove. The linker region that joins these domains is partly disordered. (Adapted from J.D. Klemm et al.. Cell 77 21-32, 1994.)...

Both domains of the POU region bind to DNA by the usual combination of non specific binding to the DNA backbone and specific binding to the bases. The contacts between the homeodomain and DNA are similar to those of the engrailed homeodomain (compare Figures 9.10b and 9.15a) and the... 

The classic zinc fingers bind to DNA in tandem along the major groove... 

Figure 10.5 Comparison of the sequence-specific binding to DNA of six different zinc fingers. Residues in the N-terminus of the a helix in the finger regions are numbered 1 to 6. The residue immediately preceding the a helix is numbered -1. Amino acid residues and nucleotides that make sequence-specific contacts are colored. In spite of the structural similarities between the zinc fingers and their overall mode of binding, there is no simple rule that governs which bases the fingers contact.

The individual domains of the two receptors both have structures similar to that of the glucocorticoid receptor, and they bind to DNA in a similar way, with their recognition helices in the major groove. The dimer contacts are, however, totally different. In the glucocorticoid receptor, which binds to a palindromic DNA sequence like the 434 repressor described in Chapter 8, the domains interact symmetrically in a head-to-head fashion equivalent... 

Subsequently Stephen Harrison s group determined the x-ray structure of a PPRl-DNA complex and showed that the zinc cluster domain of PPRl and its mode of binding to DNA was very similar to that of GAL4, and that PPRl also dimerized through a coiled-coil region. However, the linker region... 

Families of zinctranscription factors bind to DNA in several different ways... 

GCN4 binds to DNA with both specific and nonspecific contacts... 

Figure 10.28 Schematic diagram of the binding of the transcription factor Max to DNA. The two monomers of Max (blue and green) form a dimer through both the helix-loop-helLx regions which form a four-helix bundle like MyoD, and the zipper regions, which are arranged in a coiled coil. The N-terminal basic regions bind to DNA in a way similar to GCN4 and MyoD. (Adapted from A.R. Ferre-D Amare et al., Nature 363 38-4S, 1993.)...

---