dc.contributor.author | Bery, N | |
dc.contributor.author | Legg, S | |
dc.contributor.author | Debreczeni, J | |
dc.contributor.author | Breed, J | |
dc.contributor.author | Embrey, K | |
dc.contributor.author | Stubbs, C | |
dc.contributor.author | Kolasinska-Zwierz, P | |
dc.contributor.author | Barrett, N | |
dc.contributor.author | Marwood, R | |
dc.contributor.author | Watson, J | |
dc.contributor.author | Tart, J | |
dc.contributor.author | Overman, R | |
dc.contributor.author | Miller, A | |
dc.contributor.author | Phillips, C | |
dc.contributor.author | Minter, R | |
dc.contributor.author | Rabbitts, TH | |
dc.date.accessioned | 2020-03-04T16:33:36Z | |
dc.date.issued | 2019-06-13 | |
dc.identifier.citation | Nature communications, 2019, 10 (1), pp. 2607 - ? | |
dc.identifier.issn | 2041-1723 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/3532 | |
dc.identifier.eissn | 2041-1723 | |
dc.identifier.doi | 10.1038/s41467-019-10419-2 | |
dc.description.abstract | Inhibiting 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. | |
dc.format | Electronic | |
dc.format.extent | 2607 - ? | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | NATURE PUBLISHING GROUP | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0 | |
dc.subject | Cell Line, Tumor | |
dc.subject | Cell Membrane | |
dc.subject | Humans | |
dc.subject | Neoplasms | |
dc.subject | Isoenzymes | |
dc.subject | Histidine | |
dc.subject | Peptide Library | |
dc.subject | Antineoplastic Agents | |
dc.subject | Drug Screening Assays, Antitumor | |
dc.subject | Signal Transduction | |
dc.subject | Allosteric Site | |
dc.subject | Ankyrin Repeat | |
dc.subject | Protein Binding | |
dc.subject | Drug Design | |
dc.subject | Proto-Oncogene Proteins p21(ras) | |
dc.subject | Protein Multimerization | |
dc.subject | HEK293 Cells | |
dc.title | KRAS-specific inhibition using a DARPin binding to a site in the allosteric lobe. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2019-05-09 | |
rioxxterms.versionofrecord | 10.1038/s41467-019-10419-2 | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by/4.0 | |
rioxxterms.licenseref.startdate | 2019-06-13 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Nature communications | |
pubs.issue | 1 | |
pubs.notes | Not known | |
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.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-status | Published | |
pubs.volume | 10 | |
pubs.embargo.terms | Not known | |
icr.researchteam | Chromosomal Translocations and Intracellular Antibody Therapeutics | |
dc.contributor.icrauthor | Rabbitts, Terence | |