▲ FIGURE 4-3 The DNA double helix. (a) Space-filling model of B DNA, the most common form of DNA in cells. The bases (light shades) project inward from the sugar-phosphate backbones (dark red and blue) of each strand, but their edges are accessible through major and minor grooves. Arrows indicate the 5'n3' direction of each strand. Hydrogen bonds between the bases are in the center of the structure. The major and minor grooves of the double helix. Hydrophobic and van der Waals interactions between the stacked adjacent base pairs further stabilize the double-helical structure.

In natural DNA, A always hydrogen bonds with T and G with C, forming A-T and G-C base pairs as shown in Figure 4-3b. These associations between a larger purine and smaller pyrimidine are often called Watson-Crick base pairs. Two polynucleotide strands, or regions thereof, in which all the nucleotides form such base pairs are said to be complementary. However, in theory and in synthetic DNAs other base pairs can form. For example, a guanine (a purine) could theoretically form hydrogen bonds with a thymine (a pyrimidine), causing only a minor distortion in the helix. The space available in the helix also would allow pairing between the two pyrimidines cytosine and thymine. Although the nonstandard G-T and C-T base pairs are normally not found in DNA, G-U base pairs are quite common in double-helical regions that form within otherwise single-stranded RNA.

Most DNA in cells is a right-handed helix. The x-ray diffraction pattern of DNA indicates that the stacked bases are regularly spaced 0.36 nm apart along the helix axis. The are lined by potential hydrogen bond donors and acceptors (highlighted in yellow). (b) Chemical structure of DNA double helix. This extended schematic shows the two sugar-phosphate backbones and hydrogen bonding between the Watson-Crick base pairs, A-T and G-C. [Part (a) from R. Wing et al., 1980, Nature 287:755; part (b) from R. E. Dickerson, 1983, Sci. Am. 249:94.]

helix makes a complete turn every 3.6 nm; thus there are about 10.5 pairs per turn. This is referred to as the B form of DNA, the normal form present in most DNA stretches in cells. On the outside of B-form DNA, the spaces between the intertwined strands form two helical grooves of different widths described as the major groove and the minor groove (see Figure 4-3a). As a consequence, the atoms on the edges of each base within these grooves are accessible from outside the helix, forming two types of binding surfaces. DNA-binding proteins can "read" the sequence of bases in duplex DNA by contacting atoms in either the major or the minor grooves.

In addition to the major B form, three additional DNA structures have been described. Two of these are compared to B DNA in Figure 4-4. In very low humidity, the crystallo-graphic structure of B DNA changes to the A form; RNA-DNA and RNA-RNA helices exist in this form in cells and in vitro. Short DNA molecules composed of alternating purine-pyrimidine nucleotides (especially Gs and Cs) adopt an alternative left-handed configuration instead of the normal right-handed helix. This structure is called Z DNA because the bases seem to zigzag when viewed from the side. Some evidence suggests that Z DNA may occur in cells, although its function is unknown. Finally, a triple-stranded DNA structure is formed when synthetic polymers of poly(A) and

▲ FIGURE 4-4 Models of various known DNA structures.

The sugar-phosphate backbones of the two strands, which are on the outside in all structures, are shown in red and blue; the bases (lighter shades) are oriented inward. (a) The B form of DNA has =10.5 base pairs per helical turn. Adjacent stacked base pairs are 0.36 nm apart. (b) The more compact A form of DNA has 11 base pairs per turn and exhibits a large tilt of the base pairs with respect to the helix axis. (c) Z DNA is a left-handed double helix.

▲ FIGURE 4-5 Bending of DNA resulting from protein binding. The conserved C-termlnal domain of the TATA box-binding protein (TBP) binds to the minor groove of specific DNA sequences rich in A and T, untwisting and sharply bending the double helix. Transcription of most eukaryotic genes requires participation of TBP [Adapted from D. B. Nikolov and S. K. Burley, 1997, Proc. Nat'l. Acad. Sci. USA 94:15.]

polydeoxy(U) are mixed in the test tube. In addition, ho-mopolymeric stretches of DNA composed of C and T residues in one strand and A and G residues in the other can form a triple-stranded structure by binding matching lengths of synthetic poly(C+T). Such structures probably do not occur naturally in cells but may prove useful as therapeutic agents.

By far the most important modifications in the structure of standard B-form DNA come about as a result of protein binding to specific DNA sequences. Although the multitude of hydrogen and hydrophobic bonds between the bases provide stability to DNA, the double helix is flexible about its long axis. Unlike the a helix in proteins (see Figure 3-3), there are no hydrogen bonds parallel to the axis of the DNA helix. This property allows DNA to bend when complexed with a DNA-binding protein (Figure 4-5). Bending of DNA is critical to the dense packing of DNA in chromatin, the protein-DNA complex in which nuclear DNA occurs in eu-karyotic cells (Chapter 10).

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