Figure 1
From: Characterization of pathogenic germline mutations in human Protein Kinases
Consensus model structure of summarizing the human Protein Kinase family The model structure of human Protein Kinase, based on MAP3K1, shows the basic two-lobe kinase fold, with the N- and C-terminal (green and orange respectively) lobes joined by a hinge region (magenta). Substrate recognition is through interaction with the activation segment (blue), a region in the C-terminal lobe. The substrate-binding groove is located between the catalytic loop, the P+1 loop (activation segment), helix D, helix F, helix G and helix H. ATP binds at a site between the two lobes (yellow) that includes five conserved residues: (i) Lysine 74 that interacts with the alpha and beta phosphates of ATP and thereby stabilizing it; (ii) a nearby glutamic acid (E96) forms a salt bridge with lysine 74 increasing the stabilization network; (iii) Aspartate 171 is the catalytic base that initiates phosphotransfer by deprotonating the acceptor serine, threonine or tyrosine; (iv) Asparagine 176 interacts with a secondary divalent cation, thereby positioning the gamma-phosphate of ATP, and finally (v) Aspartate 190 which chelates the primary divalent cation, indirectly positioning ATP at the same time.