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dc.contributor.authorHealy, Alan
dc.contributor.authorHouston, Douglas R.
dc.contributor.authorRemnant, Lucy
dc.contributor.authorHuart, Anne-Sophie
dc.contributor.authorBrychtova, Veronika
dc.contributor.authorMaslon, Magda M.
dc.contributor.authorMeers, Olivia
dc.contributor.authorMuller, Petr
dc.contributor.authorKrecji, Adam
dc.contributor.authorBlackburn, Elizabeth M.
dc.contributor.authorVojtesek, B.
dc.contributor.authorHernychova, Lenka
dc.contributor.authorWalkinshaw, M. D.
dc.contributor.authorWestwood, Nicholas James
dc.contributor.authorHupp, Ted
dc.date.accessioned2015-04-06T15:31:02Z
dc.date.available2015-04-06T15:31:02Z
dc.date.issued2015
dc.identifier.citationHealy , A , Houston , D R , Remnant , L , Huart , A-S , Brychtova , V , Maslon , M M , Meers , O , Muller , P , Krecji , A , Blackburn , E M , Vojtesek , B , Hernychova , L , Walkinshaw , M D , Westwood , N J & Hupp , T 2015 , ' Discovery of a novel ligand that modulates the protein-protein interactions of the AAA+ superfamily oncoprotein reptin ' Chemical Science , vol. In press . https://doi.org/10.1039/C4SC03885Aen
dc.identifier.issn2041-6520
dc.identifier.otherPURE: 175561061
dc.identifier.otherPURE UUID: 61c3dec8-73c3-48fc-a4ff-d1d3b298f8cd
dc.identifier.otherScopus: 84928152626
dc.identifier.otherORCID: /0000-0003-0630-0138/work/56424189
dc.identifier.urihttp://hdl.handle.net/10023/6436
dc.descriptionFinancial support for this project was provided by Cancer Research UK (CRUK grant C21383/A6950). CRUK C483/A10706 and C483/A8033; EPSRC EP/F500421/1 doctoral training centre in cell and proteomic technologies; GACR P206/12/G151 and the state budget of the Czech Republic (LO1413).en
dc.description.abstractDeveloping 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.
dc.language.isoeng
dc.relation.ispartofChemical Scienceen
dc.rightsCopyright 2015 the Authors. This Open Access Article is licensed under a Creative Commons Attribution 3.0 Unported Licence (http://creativecommons.org/licenses/by/3.0/).en
dc.subjectQD Chemistryen
dc.subjectNDASen
dc.subject.lccQDen
dc.titleDiscovery of a novel ligand that modulates the protein-protein interactions of the AAA+ superfamily oncoprotein reptinen
dc.typeJournal articleen
dc.description.versionPostprinten
dc.description.versionPublisher PDFen
dc.contributor.institutionUniversity of St Andrews.School of Chemistryen
dc.contributor.institutionUniversity of St Andrews.EaSTCHEMen
dc.contributor.institutionUniversity of St Andrews.Biomedical Sciences Research Complexen
dc.identifier.doihttps://doi.org/10.1039/C4SC03885A
dc.description.statusPeer revieweden


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