Groove-binding

The two grooves, major and minor, in a DNA double helix are structural features that can be readily recognized by many compounds. Typically, major groove binders share distinct traits from minor groove binders. 

Unlike many DNA alkylators, cyclophosphamide shows modest selectivity for cancer cells. Healthy tissues in a patient have high levels of aldehyde dehydrogenase (ALDH). ALDH reduces the potency of cyclophosphamide by oxidizing 6.32 to 6.34, an inactive compound. Cancerous cells tend to be deficient in ALDH and more prone to damage by cyclophosphamide. 

Most groove binders have binding selectivity toward AT-rich areas, because grooves, which consist of GC base pairs, are sterically hindered by the guanine amino functionality at C-2 and its hydrogen bond with the C-2 carbonyl functionality of 

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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. 

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.)...

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. 

The investigation of minor groove-binding polyamides was greatly accelerated by the implementation of solid-phase synthesis [48]. Originally demonstrated on Boc-y9-Ala-PAM resin with Boc-protected monomers, it was also shown that Fmoc chemistry could be employed with suitably protected monomers and Fmoc-y9-Ala-Wang resin (Fig. 3.8) [49]. Recently, Pessi and coworkers used a sulfonamide-based safety-catch resin to prepare derivatives of hairpin polyamides [50]. Upon activation of the linker, resin-bound polyamides were readily cleaved with stoichiometric quantities of nucleophile to provide thioesters or peptide conjugates. 

Some purely major groove-binding TFs, such as the basic-region leucine zipper (bZIP) protein GCN4, can co-occupy the DNA helix in the presence of polyamides [72]. Modified polyamides with an attached Arg-Pro-Arg tripeptide can interfere with major groove-binding proteins by disrupting key phosphate contacts, distort-... 

B. Dervan, and J.M. Gotteseeld. Importance of minor groove binding zinc fingers within the transcription factor lllA-DNA complex./. Mol. Biol. 1997, 274, 439-445. 

Bremer, R. E., E.E. Baird, and P.B. Dervan. Inhibition of major-groove-binding proteins by pyrrole-imidazole polyamides with an Arg-Pro-Arg positive patch. 

Electrostatic binding Groove binding Intercalative binding Fig. 5 Schematic representation of various binding modes of small molecules to DNA... 

Araki K, Yoshikawa I (2005) Nucleobase-Containing Gelators. 256 133-165 Armitage BA (2005) Cyanine Dye-DNA Interactions Intercalation, Groove Binding and Aggregation. 253 55-76... 

Nature provides examples of sequence-selective minor groove binding, such as antibiotics including netropsin, distamycin, anthelvencin, and kikumycin. 

Karlsson, H.J., Eriksson, M., Perzon, E., Akerman, B., Lincoln, P., and Westman, G. (2003) Groove-binding unsymmetrical cyanine dyes for staining of DNA Syntheses and characterization of the DNA-bind-ing. Nucleic Acids Res. 31(21), 6227-6234. 

The d(A.T)-specific, minor groove binding drug NSC-101327 (Fig. 11) served as an important lead structure for the design of didiazonium com-... 

We chose to show the application of techniques employed to study supramolecular dynamics to host systems that have defined binding sites and, therefore, form host-guest complexes with defined stoichiometries. CDs were chosen because they represent a host with only one binding site, and therefore can be viewed as a model system for hosts with the lowest degree of complexity. DNA was chosen because it provides multiple binding sites for small molecules, i.e. intercalative and groove binding, while the DNA is structurally fairly well defined. 

The dynamics of intercalation of small molecules with DNA, groove binding and binding to specific sites, such as base pair mismatches have been studied by stopped-flow,23,80 108 temperature jump experiments,26,27,94 109 120 surface plasmon resonance,121 129 NMR,86,130 135 flash photolysis,136 138 and fluorescence correlation spectroscopy.64 The application of the various techniques to study the binding dynamics of small molecules will be analyzed for specific examples of each type of binding. 

Groove binding guests, binding dynamics of DNA with, 201-204 cyanine dyes, 203, 204 distamycin, 201-203, 204... 

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