Fig 1.
Binding characters of MEK-ligand complexes.
a) All MEK-ligand complex structures aligned using SMAP. b) Encoding all MEK-ligand interactions. Every row represents the MEK-ligand interaction fingerprint of one complex structure, and every column represents the interactions between the same amino acid in space and the bound ligand in different complex structures. Different colors represent the different types of fingerprint interactions: yellow, no interaction; blue, apolar interaction; red, apolar interaction + hydrogen bond interaction (protein as donor); deep red, hydrogen bond interaction (protein as donor); pink, polar interaction+ aromatic interaction; and grey, apolar interaction + hydrogen bond interaction (protein as acceptor). c) Spatial representation of MEK-ligand interactions. d) Pharmacophore modeling: H, hydrophobic group; R, aromatic ring; D, hydrogen-bond donor.
Fig 2.
Ligands from the 29 MEK-ligand complex structures.
The triangles highlight the conserved structure-activity relationships (SARs) that characterize the MEK Type-III inhibitors in 3D space.
Fig 3.
RMSF profiles and PCA projection.
a) The RMSF profiles from the last 0.5 μm equilibrated MD trajectories of MEK and the MEK-Cobimetinib complex, respectively. Some secondary structure elements are shown on the abscissa. b) and c) The Cα-atom projection along the first principal component. The displacements are shown as color-coded tubes from blue (small displacement) to orange (large displacement) for (b) MEK and (c) the MEK-Cobimetinib complex.
Fig 4.
Two conserved interatomic interactions between MEK and the ligand.
(a) Interatomic distances for every conformation from the MD trajectory; (b) The probability distribution of interatomic distances.
Fig 5.
The phylogenetic distribution of the top 15 human protein kinases where a helix was predicted in the activation loop.
The figure was generated using TREEspot (www.discoverx.com).
Table 1.
Top 15 kinases predicted with high confidence to have a helix at part of the activation loop.