Extended Data Fig. 4: Saturation mutagenesis screen reveals residues that modulate inhibition.
From: Pan-KRAS inhibitor disables oncogenic signalling and tumour growth
a,b, The effect of substitutions in amino acids involved in the drug binding interface (a) or in the RAS-GDP:SOS1 interface (b) are shown (mean ± 95%CI, n = 3). Only variants with a log FC (KRASi/DMSO) > 1 and FDR < 0.05 are included. All boxplots denote median, interquartile range and Tukey whiskers. c,d, As in a, but the cells were treated either with the inactive state selective pan KRASi or with an active state selective KRAS G12C inhibitor. The effect of substitutions in amino acids comprising the G4 and G5 motifs or substitutions in amino acids involved in contacts with the α5 helix are shown in c and d, respectively (mean ± 95%CI, n = 3). e,f, Cell extracts from HEK293 cells expressing the indicated KRAS variants were subjected to RBD-pulldown and immunoblotting to determine the effect on KRAS-GTP. g, The indicated KRAS mutants were loaded with mant-GDP and subjected to nucleotide exchange in the absence or the presence of the catalytic subunit of SOS1 or EDTA. A representative of two independent repeats is shown in e, f and g.
