Minor groove binding

Misra, V., K. Sharp, R. Friedman and B. Honig. (1994b). Salt effects on ligand-DNA binding Minor groove antibiotics. J. Mol. Biol. 238 245-263. 

V. K. Misra, K. A. Sharp, R. A. Friedman, and B. Honig, /. Molec. Biol., 238,245 (1994). Salt Effects on Ligand-DNA Binding. Minor Groove Binding Antibiotics. 

W. Wierenga "DNA-Minor Groove Binding Anticancer Agents" in Cytotoxic Mnticancer Drugs Models and Conceptsfor Drug Discovey and Development, Kluwer Academic PubHshers, Boston, Mass., 1992, p. 105. 

Lac repressor binds to both the major and the minor grooves inducing a sharp bend in the DNA... 

The polypeptide chain of the lac repressor subunit is arranged in four domains (Figure 8.21) an N-terminal DNA-hinding domain with a helix-turn-helix motif, a hinge helix which binds to the minor groove of DNA, a large core domain which binds the corepressor and has a structure very similar to the periplasmic arablnose-binding protein described in Chapter 4, and finally a C-terminal a helix which is involved in tetramerization. This a helix is absent in the PurR subunit structure otherwise their structures are very similar. 

Figure 8.22 The lac repressor molecule is a V-shaped tetramer in which each arm is a dimer containing a DNA-hinding site. The helix-tum-helix motifs (red) of each dimer bind in two successive major grooves and the hinge helices (purple) bind adjacent to each other in the minor groove between the two major groove binding sites. The four subunits of the tetramer are held together by the four C-terminal helices (yellow) which form a four helix bundle. The bound DNA fragments are bent. (Adapted from M. Lewis et al., Science 271 1247-1254, 1996.)...

Figure 8.23 The helix-turn-helix motifs of the subunits of both the PurR and the lac repressor subunits bind to the major groove of DNA with the N-terminus of the second helix, the recognition helix, pointing into the groove. The two hinge helices of each arm of the V-shaped tetramer bind adjacent to each other in the minor groove of DNA, which is wide and shallow due to distortion of the B-DNA structure. (Adapted from M.A. Schumacher et al.. Science 266 763-770, 1994.)...

Some of the procaryotic DNA-binding proteins are activated by the binding of an allosteric effector molecule. This event changes the conformation of the dimeric protein, causing the helix-tum-helix motifs to move so that they are 34 A apart and able to bind to the major groove. The dimeric repressor for purine biosynthesis, PurR, induces a sharp bend in DNA upon binding caused by insertion of a helices in the minor groove between the two... 

Schumacher, M.A., et al. Crystal structure of Lac 1 member, PurR, bound to DNA minor groove binding by a helices. Science 266 763-770, 1994. 

TBP binds in the minor groove and induces large structural changes in DNA... 

Most sequence-specific regulatory proteins bind to their DNA targets by presenting an a helix or a pair of antiparallel p strands to the major groove of DNA. Recognition of the TATA box by TBP is therefore exceptional it utilizes a concave pleated sheet protein surface that interacts with the minor groove of DNA. Since the minor groove has very few sequence-specific... 

Like Thr 124 and Thr 215, the Asn 69 and Asn 159 residues occupy equivalent positions in the two homologous motifs of TBP. By analogy with the symmetric binding of a dimeric repressor molecule to a palindromic sequence described in Chapter 8, the two motifs of TBP form symmetric sequence-specific hydrogen bonds to the quasi-palindromic DNA sequence at the center of the TATA box. The consensus TATA-box sequence has an A-T base pair at position 4, but either a T-A or an A-T base pair at the symmetry-related position 5, and the sequence is, therefore, not strictly palindromic. However, the hydrogen bonds in the minor groove can be formed equally well to an A-T base pair or to a T-A base pair, because 02 of thymine and N3 of adenine occupy nearly stereochemically equivalent positions, and it is sufficient, therefore, for the consensus sequence of the TATA box to be quasi-palindromic. 

In conclusion, one important factor that contributes to the strong affinity of TBP proteins to TATA boxes is the large hydrophobic interaction area between them. Major distortions of the B-DNA structure cause the DNA to present a wide and shallow minor groove surface that is sterically complementary to the underside of the saddle structure of the TBP protein. The complementarity of these surfaces, and in addition the six specific hydrogen bonds between four side chains from TBP and four hydrogen bond acceptors from bases in the minor groove, are the main factors responsible for causing TBP to bind to TATA boxes 100,000-fold more readily than to a random DNA sequence. 

Figure 9.10 Schematic diagrams illustrating the complex between DNA (orange) and one monomer of the homeodomain. The recognition helix (red) binds in the major groove of DNA and provides the sequence-specific interactions with bases in the DNA. The N-terminus (green) binds in the minor groove on the opposite side of the DNA molecule and arginine side chains make nonspecific interactions with the phosphate groups of the DNA. (Adapted from C.R. Kissinger et al Cell 63 579-590, 1990.)...

Figure 9.20 Diagram iliustrating the sequence-specific interactions between DNA and p53. The C-terminai a helix and loop LI of p53 bind in the major groove of the DNA. Arg 280 from the a helix and Lys 120 from LI form important specific interactions with bases of the DNA. In addition, Arg 248 from loop L3 binds to the DNA in the minor groove. (Adapted from Y. Cho et al.. Science 265 346-355, 1994.)...

Thirty percent of the tumor-derived mutations are in L3, which contains the single most frequently mutated residue, Arg 248. Clearly the interaction between DNA and the specific side chain of an arginine residue inside the minor groove is of crucial importance for the proper function of p53. It is an open question whether this interaction is needed for the recognition of specific DNA sequences, or is required for the proper distortion of the DNA structure, or a combination of both. Other residues that are frequently mutated in this region participate in interactions with loop L2 and stabilize the structures of loops L2 and L3. Mutations of these residues presumably destabilize the structure so that efficient DNA binding can no longer take place. 

TBP-TATA box complexes are known A p sheet in TBP forms the DNA-binding site TBP binds in the minor groove and induces large structural changes in DNA The interaction area between TBP and the TATA box is mainly hydrophobic Functional implications of the distortion of DNA by TBP... 

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