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Issue 8, 2016
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Tunable helicity, stability and DNA-binding properties of short peptides with hybrid metal coordination motifs

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Abstract

Given the prevalent role of α-helical motifs on protein surfaces in mediating protein–protein and protein–DNA interactions, there have been significant efforts to develop strategies to induce α-helicity in short, unstructured peptides to interrogate such interactions. Toward this goal, we have recently introduced hybrid metal coordination motifs (HCMs). HCMs combine a natural metal-binding amino acid side chain and a synthetic chelating group that are appropriately positioned in a peptide sequence to stabilize an α-helical conformation upon metal coordination. Here, we present a series of short peptides modified with HCMs consisting of a His and a phenanthroline group at i and i + 7 positions that can induce α-helicity in a metal-tunable fashion as well as direct the formation of discrete dimeric architectures for recognition of biological targets. We show that the induction of α-helicity can be further modulated by secondary sphere interactions between amino acids at the i + 4 position and the HCM. A frequently cited drawback of the use of peptides as therapeutics is their propensity to be quickly digested by proteases; here, we observe an enhancement of up to ∼100-fold in the half-lives of the metal-bound HCM-peptides in the presence of trypsin. Finally, we show that an HCM-bearing peptide sequence, which contains the DNA-recognition domain of a bZIP protein but is devoid of the obligate dimerization domain, can dimerize with the proper geometry and in an α-helical conformation to bind a cognate DNA sequence with high affinities (Kd ≥ 65 nM), again in a metal-tunable manner.

Graphical abstract: Tunable helicity, stability and DNA-binding properties of short peptides with hybrid metal coordination motifs

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Publication details

The article was received on 22 Feb 2016, accepted on 07 May 2016 and first published on 18 May 2016


Article type: Edge Article
DOI: 10.1039/C6SC00826G
Citation: Chem. Sci., 2016,7, 5453-5461
  • Open access: Creative Commons BY-NC license
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    Tunable helicity, stability and DNA-binding properties of short peptides with hybrid metal coordination motifs

    S. J. Smith, R. J. Radford, R. H. Subramanian, B. R. Barnett, J. S. Figueroa and F. A. Tezcan, Chem. Sci., 2016, 7, 5453
    DOI: 10.1039/C6SC00826G

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