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Truncation, randomisation and selection: Generation of a reduced length cJun antagonist that retains high interaction stability.

Crooks, Richard O and Rao, Tara and Mason, Jody M (2011) 'Truncation, randomisation and selection: Generation of a reduced length cJun antagonist that retains high interaction stability.' The Journal of biological chemistry, 286. pp. 29470-29479. ISSN 0021-9258

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Abstract

The DNA binding activity of the transcriptional regulator Activator Protein-1 shows considerable promise as a target in cancer therapy. A number of different strategies have been employed to inhibit the function of this protein with promise having been demonstrated both in vitro and in vivo. Peptide-based therapeutics have received renewed interest in the last few years and a number of 37 amino acid peptides capable of binding to the coiled coil dimerisation domain of Jun and Fos have been derived. Here we demonstrate how truncation and semi-rational library design, followed by protein-fragment complementation, can be used to produce a leucine zipper binding peptide by iterative means. To this end, we have implemented this strategy on the FosW peptide to produce 4hFosW. This peptide is truncated by four residues with comparably favourable binding properties and demonstrates the possibility to design progressively shorter peptides to serve as leucine zipper antagonists while retaining many of the key features of the parent peptide. Whether or not the necessity for low molecular weight antagonists is required from the perspective of druggability and efficacy is subject to debate. However, antagonists of reduced length are worthy of perusal from the point of view of synthetic cost as well as identifying the smallest functional unit that is required for binding.

Item Type: Article
Uncontrolled Keywords: AP-1 transcription factor; Circular dichroism (CD); Peptide interactions; Protein stability; Library design; coiled coil protein design
Subjects: Q Science > QD Chemistry
Q Science > QH Natural history > QH301 Biology
Divisions: Faculty of Science and Health > Biological Sciences, School of
Depositing User: Admin
Date Deposited: 06 Sep 2011 11:38
Last Modified: 16 Dec 2014 11:17
URI: http://repository.essex.ac.uk/id/eprint/21

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