Fig. 2: Structural basis for an activating MEK mutation. | Nature Communications

Fig. 2: Structural basis for an activating MEK mutation.

From: Qualitative differences in disease-associated MEK mutants reveal molecular signatures and aberrant signaling-crosstalk in cancer

Fig. 2

a Overall crystal structures of MEK1 (PDB:3EQI) and MEK1(C121S) are shown as ribbon diagrams. Color coding: dark blue, helix A (αA); orange, helix C (αC); pink, T-loop; cyan, P-loop. The positions of key residues are shown. b Close-up views of the helix C and T-loop in MEK1 and MEK1(C121S). c Local structures around WT C121 and the mutated S121. Cyan sphere, water molecule; light-blue dotted lines, H-bonds; numbers, distances in (Å). d MEK1(C121S) mutation disrupts the interdomain hydrogen (H)-bonds connecting residues H119 and F129 with K57. Superposition of the interdomain H-bonds in 14 MEK1 structures (upper) and the corresponding area in MEK1(C121S) (lower) are shown. c, d Nitrogen and oxygen atoms are colored blue and red, respectively. The numbers beside the dotted lines represent distances (Å). e Excessive outward rotation of the MEK1(C121S)-helix C. (Upper) The helix C structure of MEK1(C121S) (green) is superimposed on that of MEK1 WT (orange, PDB: 3SLS). The helix C of MEK1(C121S) is rotated out by 20 degrees relative to that of MEK1 WT. (Lower) Superposition of the C helices of MEK1(C121S) (green), MEK1 WT (grey, PDB: 3SLS), and active PKA (red, PDB: 1ATP). f Antiparallel coiled-coil interactions between the helix C and the T-loop in MEK1(C121S). (upper) The helix C interacts with a part of the T-loop that forms a helix. (lower) Residues forming hydrophobic contacts are shown. g Space-filling models. A PKA substrate peptide (yellow, PDB: 4HPU) is superimposed on the MEK1 structures.

Back to article page