Figure 7–5 Six steps at which eukaryotic gene expression can be controlled.
Controls that operate at steps 1 through 5 are discussed in this chapter. Step 6, the regulation of protein activity, occurs largely through covalent post-translational modifications including phosphorylation, acetylation, and ubiquitylation (see table 3–3, p. 165). Step 6 was introduced in Chapter 3 and is subsequently discussed in many chapters throughout the book.
Figure 7–6 Double-helical structure of DNA. A space-filling model of DnA showing the major and minor grooves on the outside of the double helix (see Movie 4.1). the atoms are colored as follows: carbon, dark blue; nitrogen, light blue; hydrogen, white; oxygen, red; phosphorus, yellow.
this structure. When first discovered in the 1960s, it was thought that these proteins might require direct access to the interior of the double helix to distinguish between one DNA sequence and another. It is now clear, however, that the outside of the double helix is studded with DNA sequence information that transcription regulators recognize: the edge of each base pair presents a distinctive pattern of hydrogen-bond donors, hydrogen-bond acceptors, and hydrophobic patches in both the major and minor grooves (Figure 7–7). Because the major groove is wider and displays more molecular features than does the minor groove, nearly all transcription regulators make the majority of their contacts with the major groove—as we shall see.
Molecular recognition in biology generally relies on an exact fit between the surfaces of two molecules, and the study of transcription regulators has provided some of the clearest examples of this principle. A transcription regulator recognizes a specific cis-regulatory sequence because the surface of the protein is extensively complementary to the special surface features of the double helix that displays that sequence. Each transcription regulator makes a series of contacts with the DNA, involving hydrogen bonds, ionic bonds, and hydrophobic interactions. Although each individual contact is weak, the 20 or so contacts that are typically formed at the protein–DNA interface add together to ensure that the interaction is both highly specific and very strong (Figure 7–8). In fact, DNA–protein
Figure 7–7 How the different base pairs in DNA can be recognized from their edges without the need to open the double helix. the four possible configurations of base pairs are shown, with potential hydrogen-bond donors indicated in blue, potential hydrogen-bond acceptors in red, and hydrogen bonds of the base pairs themselves as a series of short, parallel red lines. Methyl groups, which form hydrophobic protuberances, are shown in yellow, and hydrogen atoms that are attached to carbons, and are therefore unavailable for hydrogen-bonding, are white. from the major groove, each of the four base-pair configurations projects  a unique pattern of features. (from
C. Branden and J. tooze, introduction to protein Structure, 2nd ed. new York: Garland publishing, 1999.) outer limit of sugar-phosphate of DNAbackbone on outside of double helix interactions include some of the tightest and most specific molecular interactions known in biology.
Although each example of protein–DNA recognition is unique in detail, x-ray crystallographic and nuclear magnetic resonance (NMR) spectroscopic studies of hundreds of transcription regulators have revealed that many of them contain one or another of a small set of DNA-binding structural motifs (Panel 7–1). These motifs generally use either α helices or β sheets to bind to the major groove of DNA. The amino acid side chains that extend from these protein motifs make the specific contacts with the DNA. Thus, a given structural motif can be used to recognize many different cis-regulatory sequences depending on the specific side chains present.
Dimerization of transcription regulators increases their Affinity and Specificity for DnA