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dc.contributor.authorBery, Nen_US
dc.contributor.authorLegg, Sen_US
dc.contributor.authorDebreczeni, Jen_US
dc.contributor.authorBreed, Jen_US
dc.contributor.authorEmbrey, Ken_US
dc.contributor.authorStubbs, Cen_US
dc.contributor.authorKolasinska-Zwierz, Pen_US
dc.contributor.authorBarrett, Nen_US
dc.contributor.authorMarwood, Ren_US
dc.contributor.authorWatson, Jen_US
dc.contributor.authorTart, Jen_US
dc.contributor.authorOverman, Ren_US
dc.contributor.authorMiller, Aen_US
dc.contributor.authorPhillips, Cen_US
dc.contributor.authorMinter, Ren_US
dc.contributor.authorRabbitts, THen_US
dc.date.accessioned2020-03-04T16:33:36Z
dc.date.issued2019-06-13en_US
dc.identifier.citationNature communications, 2019, 10 (1), pp. 2607 - ?en_US
dc.identifier.issn2041-1723en_US
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/3532
dc.identifier.eissn2041-1723en_US
dc.identifier.doi10.1038/s41467-019-10419-2en_US
dc.description.abstractInhibiting the RAS oncogenic protein has largely been through targeting the switch regions that interact with signalling effector proteins. Here, we report designed ankyrin repeat proteins (DARPins) macromolecules that specifically inhibit the KRAS isoform by binding to an allosteric site encompassing the region around KRAS-specific residue histidine 95 at the helix α3/loop 7/helix α4 interface. We show that these DARPins specifically inhibit KRAS/effector interactions and the dependent downstream signalling pathways in cancer cells. Binding by the DARPins at that region influences KRAS/effector interactions in different ways, including KRAS nucleotide exchange and inhibiting KRAS dimerization at the plasma membrane. These results highlight the importance of targeting the α3/loop 7/α4 interface, a previously untargeted site in RAS, for specifically inhibiting KRAS function.en_US
dc.formatElectronicen_US
dc.format.extent2607 - ?en_US
dc.languageengen_US
dc.language.isoengen_US
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en_US
dc.subjectCell Line, Tumoren_US
dc.subjectCell Membraneen_US
dc.subjectHumansen_US
dc.subjectNeoplasmsen_US
dc.subjectIsoenzymesen_US
dc.subjectHistidineen_US
dc.subjectPeptide Libraryen_US
dc.subjectAntineoplastic Agentsen_US
dc.subjectDrug Screening Assays, Antitumoren_US
dc.subjectSignal Transductionen_US
dc.subjectAllosteric Siteen_US
dc.subjectAnkyrin Repeaten_US
dc.subjectProtein Bindingen_US
dc.subjectDrug Designen_US
dc.subjectProto-Oncogene Proteins p21(ras)en_US
dc.subjectProtein Multimerizationen_US
dc.subjectHEK293 Cellsen_US
dc.titleKRAS-specific inhibition using a DARPin binding to a site in the allosteric lobe.en_US
dc.typeJournal Article
dcterms.dateAccepted2019-05-09en_US
rioxxterms.versionofrecord10.1038/s41467-019-10419-2en_US
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0en_US
rioxxterms.licenseref.startdate2019-06-13en_US
rioxxterms.typeJournal Article/Reviewen_US
dc.relation.isPartOfNature communicationsen_US
pubs.issue1en_US
pubs.notesNot knownen_US
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Chromosomal Translocations and Intracellular Antibody Therapeutics
pubs.publication-statusPublisheden_US
pubs.volume10en_US
pubs.embargo.termsNot knownen_US
icr.researchteamChromosomal Translocations and Intracellular Antibody Therapeuticsen_US
dc.contributor.icrauthorRabbitts, Terenceen_US


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