Design and Synthesis of a Peptide That Binds Specific DNA Sequences through Simultaneous Interaction in the Major and in the Minor Groove

Vázquez, M. Eugenio; Caamaño, Ana M.; Martı́nez-Costas, José; Castedo, Luís; Mascareñas, José L.

doi:10.1002/1521-3773(20011217)40:24<4723::aid-anie4723>3.0.co;2-l

Cited by 55 publications

(15 citation statements)

References 25 publications

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“…In addition to the straightforward substitutions of the dimerization domain described before, the GCN4 bZIP-binding domain has inspired the development of a variety of synthetic, sequenceselective DNA-binding peptides [28][29][30][31][32][33][34] . Interestingly, although in all naturally occurring bZIP proteins the basic region is positioned N-terminal to the leucine zipper, Oakley and coworkers 35 showed that model 'reverse' bZIP peptides, in which the basic region of the bZIP factor GCN4 is placed C-terminal to its leucine zipper, can specifically bind to inverted DNA sites.…”

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confidence: 99%

Stimuli-responsive selection of target DNA sequences by synthetic bZIP peptides

Mosquera¹,

Jiménez-Balsa²,

Dodero³

et al. 2013

Nat Commun

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One of the strategies used by nature to regulate gene expression relies on the stimulicontrolled combination of DNA-binding proteins. This in turn determines the target-binding site within the genome, and thereby whether a particular gene is activated or repressed. Here we demonstrate how a designed basic region leucine zipper-based peptide can be directed towards two different DNA sequences depending on its dimerization arrangement. While the monomeric peptide is non-functional, a C-terminal metallo-dimer recognizes the natural ATF/CREB-binding site (5 0 -ATGA cg TCAT-3 0 ), and a N-terminal disulphide dimer binds preferentially to the swapped sequence (5 0 -TCAT cg ATGA-3 0 ). As the dimerization mode can be efficiently controlled by appropriate external reagents, it is possible to reversibly drive the peptide to either DNA site in response to such specific inputs. This represents the first example of a designed molecule that can bind to more than one specific DNA sequence depending on changes in its environment.

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mentioning

confidence: 99%

Stimuli-responsive selection of target DNA sequences by synthetic bZIP peptides

Mosquera¹,

Jiménez-Balsa²,

Dodero³

et al. 2013

Nat Commun

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“…The tripyrrole unit was prepared following reported procedures [13]. Selective functionalization at K296, required to attach the minor groove binding moiety, was performed through the introduction of an Alloc-protected side chain lysine residue [23].…”

Section: Resultsmentioning

confidence: 99%

“…A peptide corresponding to the DNA recognition helix of HPV-16 E2 displays only residual structure and binds DNA with low affinity [11], [12]. Recently, it was demonstrated in various biological systems that the appropriate tethering of a monomeric DNA-binding helix to a distamycin ( Dst )-like tripyrrole, which binds with moderate affinity the minor groove adjacent to the helix target site, provides for specific binding [13], [14], [15]. The natural cognate DNAs of HPV-16 and -18 E2 present, in the region adjacent to the DNA-sequence recognized by E2 (CGGT), the sequence AAAT, which is one of the sequences with the highest binding affinities for Dst [16].…”

Section: Introductionmentioning

confidence: 99%

New Human Papilloma Virus E2 Transcription Factor Mimics: A Tripyrrole-Peptide Conjugate with Tight and Specific DNA-Recognition

Wetzler

Comin²,

Krajewski

et al. 2011

PLoS ONE

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BackgroundHuman papillomavirus (HPV) is the main causative agent of cervical cancer, particularly high risk strains such us HPV-16, -18 and -31. The viral encoded E2 protein acts as a transcriptional modulator and exerts a key role in viral DNA replication. Thus, E2 constitutes an attractive target for developing antiviral agents. E2 is a homodimeric protein that interacts with the DNA target through an α-helix of each monomer. However, a peptide corresponding to the DNA recognition helix of HPV-16 E2 binds DNA with lower affinity than its full-length DNA binding domain. Therefore, in an attempt to promote the DNA binding of the isolated peptide, we have designed a conjugate compound of the E2 α-helix peptide and a derivative of the antibiotic distamycin, which involves simultaneous minor- and major-groove interactions.Methodology/Principal FindingsAn E2 α-helix peptide-distamycin conjugate was designed and synthesized. It was characterized by NMR and CD spectroscopy, and its DNA binding properties were investigated by CD, DNA melting and gel shift experiments. The coupling of E2 peptide with distamycin does not affect its structural properties. The conjugate improves significantly the affinity of the peptide for specific DNA. In addition, stoichiometric amounts of specific DNA increase meaningfully the helical population of the peptide. The conjugate enhances the DNA binding constant 50-fold, maintaining its specificity.Conclusions/SignificanceThese results demonstrate that peptide-distamycin conjugates are a promising tool to obtain compounds that bind the E2 target DNA-sequences with remarkable affinity and suggest that a bipartite major/minor groove binding scaffold can be a useful approach for therapeutic treatment of HPV infection.

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“…6 Curiously, while the photoactivation of biological functions has been widely applied, the inverse approach charged N-terminal basic region (br) that makes specific contacts with the DNA major groove, and a C-terminal coiled-coil leucine zipper domain that mediates dimerization. 15 It is known that monomeric basic regions do not interact with significant affinity with their DNA targets, unless they are linked to other DNA binders, 16 or engineered into prefolded constructs. 17 Alternatively, it is also possible to obtain efficient DNA binders by replacing the leucine zipper dimerization domain with artificial connectors.…”

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confidence: 99%