Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we'll assume that you are happy to receive all cookies and you won't see this message again. Click 'Find out more' for information on how to change your cookie settings.

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.

Original publication




Journal article


Nat Commun

Publication Date





Allosteric Site, Ankyrin Repeat, Antineoplastic Agents, Cell Line, Tumor, Cell Membrane, Drug Design, Drug Screening Assays, Antitumor, HEK293 Cells, Histidine, Humans, Isoenzymes, Neoplasms, Peptide Library, Protein Binding, Protein Multimerization, Proto-Oncogene Proteins p21(ras), Signal Transduction