Figure 2: Structural modelling of K-Ras switch 2 duplications.
From: KRAS insertion mutations are oncogenic and exhibit distinct functional properties
(a) Aggregate ribbon model depicting Ras (green, α2 helix in black) in its GTP-bound state, and 20 different possible orientations of the duplicated amino acids of switch 2 (rainbow). The inset shows predicted conformations of Q61; in most cases, Q61 is disordered, consistent with an active state switch 2 and reduced rate of intrinsic hydrolysis13. (b) Structural model from panel (a) superimposed into the co-crystal of the Ras/Ras–GAP (space filling) complex (PDB:1WQ1) showing steric interference at the binding interface; primary conflict is with α6 helix of GAP (inset). (c) Ras switch 2 mutant model in the context of Ras/PI3K interaction (PDB:1HE8). The extended helix does not provide a major steric impediment to binding face, but may disrupt orientation of specific interaction residues. (d) The extended helix is not predicted to perturb Raf binding to switch 1 (PDB:4G0N).
