Structure-Functional Prediction and Analysis of Cancer Mutation Effects in Protein Kinases
Figure 1
Structural analysis of the Cdk/Src kinases. The crystal structure alignment of the Cdk/Src kinases is presented separately for 3 groups of evolutionary related kinases. A diverse spectrum of the Cdk/Src kinases has a common structural determinant: the regulatory αC-helix assumes a αC-out conformation and prohibits the formation of the catalytically competent form. (a) The inactive crystal structures of Abl (pdb id 2G1T), Csk (pdb id 1BYG), Hck (pdb id 2HCK, 1AD5), Src (pdb id 2PTK, 1KSW, 1FMK), Btk (pdb id 3GEN, 3OCT), Itk (pdb id 3QGY, 1SM2), and BMX kinases (pdb id 3SXS). A close-up view of the αC-helix region in these structures (d). (b) The inactive structures of EGFR (pdb 1XKK, 2GS7), Her2 (pdb id 3PP0, 3RCD), Her3 (pdb id 3LMG,3KEX), Her4 (pdb id 2R4B, 3BBT, 3BCE), Tyk2 (pdb id 3NYX), Tie2 (pdb 2OSC), Met (pdb 2G15), Ron (pdb 3PLS), and Mer kinases (pdb id 2P0C). A close-up view of the αC-helix region in these structures (e). The remaining Cdk/Src crystal structures, representing distinct branches of the kinome tree, were assembled into one group. (c) The inactive structures of Cdk4 (pdb id 3G33), Cdk7 (pdb id 1UA2), Nek2 (pdb id 2W5H), Nek7 (pdb id 2WQM), MPSK (pdb 3DBQ), IRE1 (pdb id 2RIO), KSR2 (pdb id 2Y4I), ILK (pdb id 3KMU), WNK1 (pdb id 3FPQ), RSK1 (pdb id 2Z7S), OSR1 (pdb id 2VWI), MST4 (pdb id 3GGF), and CAMK1D (pdb 2JC6). A close-up view of the αC-helix region in these structures (f). The protein kinase structures are colored according to their secondary structure. The inactive position of the αC-helix-out is highlighted (colored in green). A close-up view highlights structural rigidity of the αC-β4 loop and certains variability of the αC-helix within the catalytically inactive position.
