Skip to main content
. Author manuscript; available in PMC: 2022 Nov 25.
Published in final edited form as: Nature. 2022 Jul 13;609(7926):408–415. doi: 10.1038/s41586-022-04928-2

Extended Data Figure 11. Druggability analysis of SHOC2 holophosphatase complex and schematic diagram of proposed model for SHOC2 holophosphatase complex assembly.

Extended Data Figure 11

a, SiteMap analysis of SHOC2 complex identifying druggable binding pockets between SHOC2-PP1C, b, SHOC2-MRAS and c, PP1C-MRAS. d, SiteScore is capped at 1.0 to limit the impact of hydrophilicity in charged and highly polar sites. A SiteScore of 0.80 has been found to accurately distinguish between drug-binding and non-drug-binding sites. For Dscore, the hydrophilic score is not capped. This one of the keys for distinguishing “difficult” and “undruggable” targets from “druggable” ones. e, Hypothesized model of the SHOC2 holophosphatase complex. MRAS is GDP bound and PP1C and SHOC2 exist in bound/unbound equilibrium in cytoplasm. Upon RTK stimulation and MRAS-GTP activation, the SHOC2-PP1C complex binds with MRAS at the plasma membrane to produce stable complex formation, and likely localizes the SHOC2 holophosphatase to lipid domains with concentrated RAS-bound RAF1 to dephosphorylate ‘S259’ on RAF and enable MAPK signaling.