Fig. 6: Structural analysis demonstrated that I141_C142delinsEI causes steric hindrance while A372del potentially alters conformation at the PPI interface.
From: The identification of functional regions of MEK1 using CRISPR tiling screens
a Mapping electrostatic potentials to the inhibitor binding pocket. Both structures of the MEK1 wild-type and I141_C142delinsEI variant are homology models. The small molecule binimetinib is superimposed from the MEK1 crystal structure (PDB code: 7M0U). Surface area of the pocket was coloured by electrostatic potentials in red (negatively charged) or blue (positively charged). The residues at position 141 are labelled. b Conformational changes between the di-phosphorylated and non-phosphorylated forms of simulated MEK1 wild-type and A372del ensembles by MD. The structures are the mean of the representative conformations of the di-phosphorylated forms. The colours mapped on the structures correspond to the DHES values. The higher the DHES value, the higher the magnitude of the conformational change. The dark blue colours correspond to the minimum observed values. c The conformational changes, represented by DHES, were mapped to the crystal structure of the MEK1-BRAF complex (PDB code: 7M0Y). The same colouring was used as in b. d Conformational difference between each of the simulated ensemble and the active MEK1 crystal structure. C-alpha RMSD distributions were obtained by comparing the trajectories of each ensemble with the S218D/S222D double mutant MEK1 crystal structure (PDB code: 4ANB). Residues across the whole MEK1 protein were compared. Mean of RMSD from three replicates is indicated in solid line. The shades represent error with 95% confidence interval obtained with bootstrapping.
