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Issue 5, 2015
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Discovery of a novel ligand that modulates the protein–protein interactions of the AAA+ superfamily oncoprotein reptin

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Abstract

Developing approaches to discover protein–protein interactions (PPIs) remains a fundamental challenge. A chemical biology platform is applied here to identify novel PPIs for the AAA+ superfamily oncoprotein reptin. An in silico screen coupled with chemical optimization provided Liddean, a nucleotide-mimetic which modulates reptin's oligomerization status, protein-binding activity and global conformation. Combinatorial peptide phage library screening of Liddean-bound reptin with next generation sequencing identified interaction motifs including a novel reptin docking site on the p53 tumor suppressor protein. Proximity ligation assays demonstrated that endogenous reptin forms a predominantly cytoplasmic complex with its paralog pontin in cancer cells and Liddean promotes a shift of this complex to the nucleus. An emerging view of PPIs in higher eukaryotes is that they occur through a striking diversity of linear peptide motifs. The discovery of a compound that alters reptin's protein interaction landscape potentially leads to novel avenues for therapeutic development.

Graphical abstract: Discovery of a novel ligand that modulates the protein–protein interactions of the AAA+ superfamily oncoprotein reptin

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Publication details

The article was received on 15 Dec 2014, accepted on 20 Mar 2015 and first published on 20 Mar 2015


Article type: Edge Article
DOI: 10.1039/C4SC03885A
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Citation: Chem. Sci., 2015,6, 3109-3116
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    Discovery of a novel ligand that modulates the protein–protein interactions of the AAA+ superfamily oncoprotein reptin

    A. R. Healy, D. R. Houston, L. Remnant, A. Huart, V. Brychtova, M. M. Maslon, O. Meers, P. Muller, A. Krejci, E. A. Blackburn, B. Vojtesek, L. Hernychova, M. D. Walkinshaw, N. J. Westwood and T. R. Hupp, Chem. Sci., 2015, 6, 3109
    DOI: 10.1039/C4SC03885A

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