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KRAS-specific inhibition using a DARPin binding to a site in the allosteric lobe

DOI: 10.1038/s41467-019-10419-2 DOI Help

Authors: Nicolas Bery (University of Oxford) , Sandrine Legg (AstraZeneca) , Judit Debreczeni (AstraZeneca) , Jason Breed (AstraZeneca) , Kevin Embrey (AstraZeneca) , Christopher Stubbs (AstraZeneca) , Paulina Kolasinska-zwierz (AstraZeneca) , Nathalie Barrett (AstraZeneca) , Rose Marwood (AstraZeneca) , Jo Watson (AstraZeneca) , Jon Tart (AstraZeneca) , Ross Overman (AstraZeneca) , Ami Miller (University of Oxford) , Christopher Phillips (AstraZeneca) , Ralph Minter (AstraZeneca) , Terence H. Rabbitts (University of Oxford)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Nature Communications , VOL 10 , PAGES 2607

State: Published (Approved)
Published: June 2019

Open Access Open Access

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.

Journal Keywords: Cancer; Drug discovery; Molecular biology; X-ray crystallography

Subject Areas: Biology and Bio-materials, Medicine


Instruments: I03-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength)

Documents:
s41467-019-10419-2.pdf