A novel β-hairpin peptide derived from the ARC repressor selectively interacts with the major groove of B-DNA.

Abstract

Transcription factors (TFs) have a remarkable role in the homeostasis of the organisms and there is a growing interest in how they recognize and interact with specific DNA sequences. TFs recognize DNA using a variety of structural motifs. Among those, the ribbon-helix-helix (RHH) proteins, exemplified by the MetJ and ARC repressors, form dimers that insert antiparallel β-sheets into the major groove of DNA. A great chemical challenge consists of using the principles of DNA recognition by TFs to design minimized peptides that maintain the DNA affinity and specificity characteristics of the natural counterparts. In this context, a peptide mimic of an antiparallel β-sheet is very attractive since it can be obtained by a single peptide chain folding in a β-hairpin structure and can be as short as 14 amino acids or less. Herein, we designed eight linear and two cyclic dodeca-peptides endowed with β-hairpins. Their DNA binding properties have been investigated using fluorescence spectroscopy together with the conformational analysis through circular dichroism and solution NMR. We found that one of our peptides, peptide 6, is able to bind DNA, albeit without sequence selectivity. Notably, it shows a topological selectivity for the major groove of the DNA which is the interaction site of ARC and many other DNA-binding proteins. Moreover, we found that a type I' β-hairpin folding pattern is a favorite peptide structure for interaction with the B-DNA major groove. Peptide 6 is a valuable lead compound for the development of novel analogs with sequence selectivity.

• Authors: Azzurra Stefanucci, Jussara Amato, Diego Brancaccio, Bruno Pagano, Antonio Randazzo, Federica Santoro, Laura Mayol, Soraya Learte-Aymamí, Jessica Rodriguez, José Luis Mascareñas, Ettore Novellino, Alfonso Carotenuto, Adriano Mollica
• Journal: Bioorganic chemistry (Bioorg Chem) Vol. 112 Pg. 104836 (07 2021) ISSN: 1090-2120 [Electronic] United States
• PMID: 33812270 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 Elsevier Inc. All rights reserved.

Chemical References

• DNA, B-Form
• Peptides
• Transcription Factors

Topics

• DNA, B-Form (chemistry)
• Molecular Structure
• Peptides (chemical synthesis, chemistry)
• Transcription Factors (chemistry)