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Discovery of a novel ligand that modulates the protein–protein interactions of the AAA+ superfamily oncoprotein reptin
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...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Royal Society of Chemistry
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5490336/ https://www.ncbi.nlm.nih.gov/pubmed/28706685 http://dx.doi.org/10.1039/c4sc03885a |
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author | Healy, Alan R. Houston, Douglas R. Remnant, Lucy Huart, Anne-Sophie Brychtova, Veronika Maslon, Magda M. Meers, Olivia Muller, Petr Krejci, Adam Blackburn, Elizabeth A. Vojtesek, Borek Hernychova, Lenka Walkinshaw, Malcolm D. Westwood, Nicholas J. Hupp, Ted R. |
author_facet | Healy, Alan R. Houston, Douglas R. Remnant, Lucy Huart, Anne-Sophie Brychtova, Veronika Maslon, Magda M. Meers, Olivia Muller, Petr Krejci, Adam Blackburn, Elizabeth A. Vojtesek, Borek Hernychova, Lenka Walkinshaw, Malcolm D. Westwood, Nicholas J. Hupp, Ted R. |
author_sort | Healy, Alan R. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-5490336 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Royal Society of Chemistry |
record_format | MEDLINE/PubMed |
spelling | pubmed-54903362017-07-13 Discovery of a novel ligand that modulates the protein–protein interactions of the AAA+ superfamily oncoprotein reptin Healy, Alan R. Houston, Douglas R. Remnant, Lucy Huart, Anne-Sophie Brychtova, Veronika Maslon, Magda M. Meers, Olivia Muller, Petr Krejci, Adam Blackburn, Elizabeth A. Vojtesek, Borek Hernychova, Lenka Walkinshaw, Malcolm D. Westwood, Nicholas J. Hupp, Ted R. Chem Sci Chemistry 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. Royal Society of Chemistry 2015-05-01 2015-03-20 /pmc/articles/PMC5490336/ /pubmed/28706685 http://dx.doi.org/10.1039/c4sc03885a Text en This journal is © The Royal Society of Chemistry 2015 http://creativecommons.org/licenses/by/3.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution 3.0 Unported License (http://creativecommons.org/licenses/by/3.0/) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Chemistry Healy, Alan R. Houston, Douglas R. Remnant, Lucy Huart, Anne-Sophie Brychtova, Veronika Maslon, Magda M. Meers, Olivia Muller, Petr Krejci, Adam Blackburn, Elizabeth A. Vojtesek, Borek Hernychova, Lenka Walkinshaw, Malcolm D. Westwood, Nicholas J. Hupp, Ted R. Discovery of a novel ligand that modulates the protein–protein interactions of the AAA+ superfamily oncoprotein reptin |
title | Discovery of a novel ligand that modulates the protein–protein interactions of the AAA+ superfamily oncoprotein reptin
|
title_full | Discovery of a novel ligand that modulates the protein–protein interactions of the AAA+ superfamily oncoprotein reptin
|
title_fullStr | Discovery of a novel ligand that modulates the protein–protein interactions of the AAA+ superfamily oncoprotein reptin
|
title_full_unstemmed | Discovery of a novel ligand that modulates the protein–protein interactions of the AAA+ superfamily oncoprotein reptin
|
title_short | Discovery of a novel ligand that modulates the protein–protein interactions of the AAA+ superfamily oncoprotein reptin
|
title_sort | discovery of a novel ligand that modulates the protein–protein interactions of the aaa+ superfamily oncoprotein reptin |
topic | Chemistry |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5490336/ https://www.ncbi.nlm.nih.gov/pubmed/28706685 http://dx.doi.org/10.1039/c4sc03885a |
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