Review: Precision medicine and driver mutations: Computational methods, functional assays and conformational principles for interpreting cancer drivers
Fig 8
Ras activation and oncogenic mutations.
(A) KRas4B is activated by the son of sevenless 1 (SOS1) nucleotide exchange factor (GEF), while GAP inactivates KRas4B via the GTP → GDP hydrolysis. KRas4B oncogenic mutations at the active site Gly12, Gly13, and Gln61 aborts the hydrolysis reaction, keeping the Ras in a constitutively active GTP-bound state. (B) Of those with mutant Ras, KRas is the most highly mutated in cancer. In KRas mutation, Gly12 mutations are the most frequent. (C) The interactions of KRas4B with the anionic membrane composed of DOPC:DOPS (4:1 molar ratio). In the active GTP-bound state, the HVR is in contact with the membrane, but the catalytic domain is away, exposing the effector binding site. In contrast, autoinhibition persists in the inactive GDP-bound state with occluded catalytic domain conformation, yielding the effector binding site is inaccessible. In cartoons, the modeled KRas4B structures were adopted from our simulations [182, 285]. DOPC, 1,2-dioleoyl-sn-glycero-3-phosphocholine; DOPS, 1,2-dioleoyl-sn-glycero-3-phospho-L-serine; GAP, GTPase-activating protein; GEF, Guanine nucleotide exchange factors; HVR, hyper variable region; SOS1, son of sevenless 1.