| Autor: |
Smith SJ; Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Dr., La Mia, USA., Radford RJ; Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Dr., La Mia, USA., Subramanian RH; Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Dr., La Mia, USA., Barnett BR; Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Dr., La Mia, USA., Figueroa JS; Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Dr., La Mia, USA., Tezcan FA; Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Dr., La Mia, USA. |
| Abstrakt: |
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 with 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-lifes 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 (K d ≥ 65 nM), again in a metal-tunable manner. |
