KRAS-specific inhibition using a DARPin binding to a site in the allosteric lobe
| Autor: | Bery, N, Legg, S, Debreczeni, J, Breed, J, Embrey, K, Stubbs, C, Kolasinska-Zwierz, P, Barrett, N, Marwood, R, Watson, J, Tart, J, Overman, R, Miller, A, Phillips, C, Minter, R, Rabbitts, T |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
endocrine system diseases
Molecular biology Science Antineoplastic Agents Article Proto-Oncogene Proteins p21(ras) Peptide Library Cell Line Tumor Neoplasms Humans Histidine lcsh:Science neoplasms X-ray crystallography Cancer Drug discovery Cell Membrane digestive system diseases respiratory tract diseases Ankyrin Repeat Isoenzymes HEK293 Cells Drug Design lcsh:Q Drug Screening Assays Antitumor Protein Multimerization Allosteric Site Protein Binding Signal Transduction |
| Zdroj: | Nature Communications, Vol 10, Iss 1, Pp 1-11 (2019) Nature Communications |
| ISSN: | 2041-1723 |
| Popis: | 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. Mutant RAS family members occur in a wide range of tumour types, and there is a great interest in identifying isoform-specific inhibitors. Here, the authors characterise two designed ankyrin repeat proteins (DARPins) that specifically inhibit the KRAS isoform by binding to the region around the KRAS-specific residue histidine 95 and show that they affect KRAS/effector interactions in different ways. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|