Controlling Binding Orientation in Hairpin Polyamide DNA Complexes

Hawkins, Cheryl A.; Clairac, Rafael Peláez de; Dominey, Raymond N.; Baird, Eldon E.; White, S.W.; Dervan, Peter B.; Wemmer, David E.

doi:10.1021/ja0001198

Cited by 38 publications

(55 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A dodecamer, CGACTGCAGTCG, contained three binding sites: two maximum overlap sites, 5Ј-ACT-3Ј and 5Ј-AGT-3Ј, and a further conceivable site, 3Ј-ACGT-5Ј, in the one residue stagger mode. But, reading in the reverse direction, 3Ј to 5Ј has been reported to occur only under special conditions, e.g., N-terminal acetylation or addition of a glycine into the tail region (41). Side-by-side polyamides tend to always read in a 5Ј to 3Ј direction.…”

Section: Resultsmentioning

confidence: 99%

DNA sequence recognition in the minor groove by crosslinked polyamides: The effect of N-terminal head group and linker length on binding affinity and specificity

O’Hare

Mack

Tandon

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Development of sequence-reading polyamides or ''lexitropsins'' with comparable DNA-binding affinities to cellular proteins raises the possibility of artificially regulated gene expression. Covalent linkage of polyamide ligands, with either a hairpin motif or crosslinking methylene bridge, has greatly improved binding affinity by ensuring their side-by-side register. Whereas hairpin polyamides have been investigated extensively, the optimized structure of crosslinked polyamides remains to be determined. This study examines a series of thiazole-imidazole-pyrrole (TIP) monomers and crosslinked dimers to evaluate the effects on selectivity and binding affinity of different N-terminal head groups attached to the leading thiazole ring and differing methylene linker lengths. Quantitative footprinting of a DNA sequence, containing potential match and mismatch sites for both maximum overlap and oneresidue stagger binding modes, allowed measurement of binding constants at each putative site. Within an N-terminal amino TIP series, C7 and C8-linked compounds bound most strongly to these sites, whereas maximum binding affinity was observed for a C6 linker with a formyl head group. A C5 linker gave weak binding with either head group. A hydrogen or acetyl head group abrogated binding. Binding was confirmed by gel shift analyses. The highest specificity for the maximum overlap site over the oneresidue stagger was observed with TIP-C7-amino. Selectivity of the leading thiazole was modulated by the head group, with Nterminal formyl TIP exhibiting up to 3-fold specificity for AGT over TGT, suggesting that N-formyl-thiazole may provide sequence discrimination of adenine over thymine. Moreover, the leading head group and methylene linker length significantly influences the binding characteristics of crosslinked polyamides.

show abstract

Section: Resultsmentioning

confidence: 99%

DNA sequence recognition in the minor groove by crosslinked polyamides: The effect of N-terminal head group and linker length on binding affinity and specificity

O’Hare

Mack

Tandon

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…In continuation of this research the importance of N-terminal acetylation and Cterminal structure of imidazole/pyrrole polyamides of type 12 on the orientation of DNA-binding (Fig. (3)) have been investigated [31]. The products were synthesized using solid-phase methods.…”

Section: Fig (3)mentioning

confidence: 99%

Advances in DNA-Ligands with Groove Binding, Intercalating and/or Alkylating Activity: Chemistry, DNA-Binding and Biology

Pindur¹,

Jansen²,

Lemster

2005

CMC

105

View full text Add to dashboard Cite

It is known that DNA is a well-characterized intracellular target but its size and sequential characteristics make it an elusive target for selective drug action. Binding of low molecular weight ligands to DNA causes a variety of significant biological responses. In this context the main consideration is given to recent developments in DNA sequence selective binding agents bearing conjugated effectors because of their potential application in treatment of cancers, in diagnosis as well as in molecular biology. In the present review recent results about analogues of netropsins, distamycin A and of some lexitropsins and combilexins or related hybrid molecules with sequence reading, intercalating or alkylating activity are described and evaluated for prospective applications. Furthermore there exists DNA minor groove binder with different basic structures which does not possess the typical polyamide chain, including dimeric intercalating chromophores. Finally new results about peptide nucleic acids and related nucleic acid bases linked with polyamides are reported. In pronounced examples the structural chemistry, synthesis, DNA binding with several biophysical methods, molecular aspects, structure activity relationship, topoisomerase inhibition, antitumour and antibacterial effects are discussed in detail.

show abstract

“…NMR studies of hairpin polyamide-DNA complexes have provided valuable insight into polyamide binding site location, stoichiometry, and binding orientation (20)(21)(22)). An NMR structure of a 6-ring GABA-linked cyclic polyamide has confirmed DNA binding and orientational preference.…”

mentioning

confidence: 99%

Allosteric modulation of DNA by small molecules

Chenoweth

Dervan

2009

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

145

178

View full text Add to dashboard Cite

Many human diseases are caused by dysregulated gene expression. The oversupply of transcription factors may be required for the growth and metastatic behavior of human cancers. Cell permeable small molecules that can be programmed to disrupt transcription factor-DNA interfaces could silence aberrant gene expression pathways. Pyrrole-imidazole polyamides are DNA minorgroove binding molecules that are programmable for a large repertoire of DNA motifs. A high resolution X-ray crystal structure of an 8-ring cyclic Py/Im polyamide bound to the central 6 bp of the sequence d(5-CCAGGCCTGG-3)2 reveals a 4 Å widening of the minor groove and compression of the major groove along with a >18°bend in the helix axis toward the major groove. This allosteric perturbation of the DNA helix provides a molecular basis for disruption of transcription factor-DNA interfaces by small molecules, a minimum step in chemical control of gene networks.

show abstract

Controlling Binding Orientation in Hairpin Polyamide DNA Complexes

Cited by 38 publications

References 27 publications

DNA sequence recognition in the minor groove by crosslinked polyamides: The effect of N-terminal head group and linker length on binding affinity and specificity

DNA sequence recognition in the minor groove by crosslinked polyamides: The effect of N-terminal head group and linker length on binding affinity and specificity

Advances in DNA-Ligands with Groove Binding, Intercalating and/or Alkylating Activity: Chemistry, DNA-Binding and Biology

Allosteric modulation of DNA by small molecules

Contact Info

Product

Resources

About