Structure-Functional Prediction and Analysis of Cancer Mutation Effects in Protein Kinases
Figure 11
Functional dynamics and structural map of cancer mutations in the inactive and active BRAF structures. Functional dynamics and conformational mobility maps of the kinase-dead mutation D594V in the inactive BRAF crystal structure, pdb id 1uwh (a) and activating V600E mutation in the active BRAF crystal structure of BRAF kinase domain, pdb id 3c4c (b). Structural distribution of the protein kinase mobility was obtained from MD simulations and is averaged over the two lowest frequency modes. The hydrophobic spine residues (F516-L505-I513-L567-H574-I572-V504) are shown in spheres. The D594V residue (a) and D594 residue (b) are shown in sticks and pointed by arrow. The F595 residue from the DFG motif is shown in spheres and annotated. The position of the BRAF selective inhibitor sorafenib (in sticks, atom-based coloring) is shown in (a). The hydrophobic spine is partially disassembled in the inactive form (a) as F595 is flipped in DFG-out position. The spine is fully assembled in the active conformation (b).
