The SII-P is very enigmatic in its nature, as it is enclosed by the highly dynamic switch-II region (Figure ) . Interestingly, a conserved water molecule, located between the b1-sheet and switch-II in SII-P, is commonly found in KRAS structures (Figure ; Table ). In this location, the conserved water is usually connected with hydrogen bonds (H-bonds) to Gly10 of b1-sheet and to the side chain hydroxyl of Thr58 of switch-II. Occasionally, a H-bond from the water to Tyr96 hydroxyl is also observed. This highly conserved water is found in this location regardless of KRAS configuration, including wild-type KRAS (Figure ), different oncogenic mutants (Figure ), as well as KRAS-effector protein complexes (Figure ). This conserved water is also present with majority of the SII-P binding KRAS inhibitors, with only a few exceptions. (A) KRAS structure with selected highlighted areas (PDB ID: 5F2E) . SII-P (green transparent surface) is enclosed by switch-II (blue cartoon) and reachable from position 12 (yellow transparent surface) located in P-loop (yellow cartoon). The conserved water (red sphere) resides in SII-P next to Thr58, Gly10 and Tyr96 (shown in sticks). This water appears in numerous KRAS crystal structures, as highlighted here with examples of electron density maps of (B) KRAS Q61H bound to GTP (PDB ID: 6MNX) , (C) KRAS WT bound to GNP (PDB ID: 6VC8) , (D) KRAS bound to GNP in complex with effector protein RAF1 (RBD) (PDB ID: 6VJJ) . Electron density (blue transparent surface) displayed at 2Fo-Fc s = 1.5.