Variant site mapping over kinase domain conformers.

The main pocket is represented as a surface. From left to right and from top to bottom: active monomer with ATP analog–peptide conjugate (PDB id 2GS6), inactive monomer with pyrimido[4,5-b]azepine-derived inhibitor (PDB id 3W32), active chain in asymmetric dimer with WZ4002 irreversible inhibitor (PDB id 3IKA_A), and inactive chain in asymmetric dimer (PDB id 3IKA_B). The most frequently affected sites (those in red, violet and dark blue) map in the catalytic pocket and are found in particular regions: the activation segment (with the classical L858R), the Gly-rich loop, and the region that connects both lobes of the kinase. Interestingly, most of the residues that serve as the docking site for the substrate peptide are not affected by variations (circled with a dashed black line). The total number of missense substitutions observed in COSMIC for each position is listed in S2 Table, column Gen_var_count_ocurrence. Missing regions are connected with straight dashed lines.