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Targeting the c‐Myc coiled coil with interfering peptides
Author(s) -
Jouaux Eva M.,
Schmidtkunz Karin,
Müller Kristian M.,
Arndt Katja M.
Publication year - 2008
Publication title -
journal of peptide science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.475
H-Index - 66
eISSN - 1099-1387
pISSN - 1075-2617
DOI - 10.1002/psc.1038
Subject(s) - peptide , coiled coil , complementation , dna , computational biology , protein fragment complementation assay , rational design , chemistry , function (biology) , biochemistry , biology , microbiology and biotechnology , genetics , gene , phenotype
Abstract c‐Myc is one of the most frequently deregulated oncogenes in human cancers, and recent studies showed that even brief inactivation of Myc can be sufficient to induce tumor regression or loss. Consequently, inactivation of Myc provides a novel therapeutic opportunity and challenge, as the dimerization of Myc with Max is crucial for its function. We applied two strategies to specifically target this coiled coil mediated interaction with interfering peptides: a dominant‐negative human Max sequence (Max) and a peptide selected from a genetic library (Mip). Both peptides form coiled coils and were fused to an acidic extension interacting with the basic DNA‐binding region of human Myc. The genetic library was obtained by semi‐rational design randomizing residues important for interaction, and selection was carried out using a protein‐fragment complementation assay. The peptides Max and Mip easily outcompeted the human Myc:Max interaction and successfully interfered with the DNA binding of the complex. Both interfering peptides exhibited higher T m (Δ T m = 13 and 15 °C) upon interaction with Myc compared to wt Max. The inhibitory effect of the two interfering peptides on human Myc:Max activity makes them promising molecules for analytical and therapeutic Myc‐directed research. Copyright © 2008 European Peptide Society and John Wiley & Sons, Ltd.