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Fig. 4 | Molecular Cancer

Fig. 4

From: Chronic myeloid leukemia: the paradigm of targeting oncogenic tyrosine kinase signaling and counteracting resistance for successful cancer therapy

Fig. 4

Regulation of the ABL1 tyrosine kinase. a All protein kinase domains have a highly conserved bilobed structure. The binding site for ATP and for the inhibitors is in a cleft between the 2 lobes. The phosphate-binding loop (P-loop) is highlighted in yellow. The phosphorylation state and conformation of the activation loop (A-loop; highlighted in red) determine whether the kinase is active or inactive. In all tyrosine kinases, the site of activating phosphorylation is generally a single Tyrosine residue located in the middle of the loop that once phosphorylated, can interact electrostatically with a neighboring Arginine residue, resulting in the stabilization of an extended and open conformation of the loop (right image). This conformation of the A-loop enables the access to the peptide substrate binding site. When the A-loop is unphosphorylated, it is folded inwards, blocking the peptide substrate binding site (left image). A second important regulatory feature of kinases is the conformation of a highly conserved aspartate-phenylalanine-glycine (DFG) motif (highlighted in orange) located at the N-terminal end of the A-loop. Images obtained with the Web-based 3D viewer NGL [113]. b Cartoon representation of ABL1 with the kinase domain (SH1), the SH2 and the SH3 domains. Alpha helices are in magenta, beta sheets in yellow. A myristic acid moiety in the myristate binding pocket is shown with a ball-and-stick representation. Binding of the myristoyl group to the myristate pocket induces a conformational change in the C-terminal helix of the kinase domain that is necessary for binding of the SH3-SH2 clamp, which keeps the kinase inactive. Image obtained with the web-based 3D viewer NGL [113] (Protein Data Bank [PDB] entry 1OPJ)

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