Receptor tyrosine kinases structure

The catalytic loop is the region of divergence between Ser/Thr and Tyr kinases. In cAPK and all Ser/Thr Kinases, Lysl68 interacts with the phosphate of ATP during catalysis [12]. The role of Lys is replaced by Arg [9] and the insulin receptor tyrosine kinase structure [3] shows Argl 136 in a similar position as Lys 168 in the active site of cAPK. 

Insulin Receptor. Figure 1 Structure and function of the insulin receptor. Binding of insulin to the a-subunits (yellow) leads to activation of the intracellular tyrosine kinase ((3-subunit) by autophosphorylation. The insulin receptor substrates (IRS) bind via a phospho-tyrosine binding domain to phosphorylated tyrosine residues in the juxtamembrane domain of the (3-subunit. The receptor tyrosine kinase then phosphorylates specific tyrosine motifs (YMxM) within the IRS. These tyrosine phosphorylated motifs serve as docking sites for some adaptor proteins with SRC homology 2 (SH2) domains like the regulatory subunit of PI 3-kinase. 

The Sema domain consisting of about 500 amino acids is characterized by highly conserved cysteine residues that form intramolecular disulfide bonds. Crystal structures have revealed that the Sema domain folds in the manner of the (3 propeller topology which is also found in integrins or the low-density lipoprotein (LDL) receptors. Sema domains are found in semaphorins, plexins and in the receptor tyrosine kinases Met and Ron. 

STRUCTURAL STUDIES OF RECEPTOR TYROSINE KINASES 4.5.1 Ligand-Binding Domains... 

Gronborg, M., Wulff, B. S., Rasmussen, J. S., Kjeldsen, T., and Gammeltoft, S., Structure-function relationship of the insulin-like growth factor-I receptor tyrosine kinase, J. Biol. Chem., 268, 23435-13440, 1993. 

Hubbard, S. R., Crystal structure of the activated insulin receptor tyrosine kinase in complex with peptide substrate and ATP analog, EMBO J., 16, 5572-5581, 1997. 

Mohammadi, M., Schlessinger, J., and Hubbard, S. R., Structure of the FGF receptor tyrosine kinase domain reveals a novel autoinhibitory mechanism, Cell, 86, 577-578, 1996. 

Wybenga-Groot, L. E. et al., Structural basis for autoinhibition of the EphB2 receptor tyrosine kinase by the unphosphorylated juxtamembrane region, Cell, 106, 745-757, 2001. 

ErbB (or HER in the human). There are four ErbB receptors that form homo- or heterodimers in various combinations upon ligand binding. Specific NRG isoforms preferentially interact with different ErbB dimers. The ErbB receptors are ligand-activated tyrosine kinases structurally similar to the EGF receptor. 

Several of the new Bcr-Abl kinase inhibitors reported subsequent to imatinib also inhibit Src, a non-receptor tyrosine kinase. In 2000, il was re-porled lhat the known Src inhibitor PD180970 (12) also inhibited Abl kinase [73] (Scheme 5). This property was soon found to be shared by several other pyrido[2,3-d]pyrimidine Src inhibitors including PD173955 (13) [74] (Scheme 5). A crystal structure of PD 173955 demonstrated that this compound could bind to both the active and inactive form of Abl [37]. While the conformation of active Src kinase is similar to that of active Abl, the conformations of the inactive kinases are quite different. Unlike PD 173955, imatinib only binds the inactive form of Abl. The inability of imatinib to inhibit Src is... 

Phosphohpases of type Cy are activated by receptor tyrosine kinases (see Chapter 8), and thus phosphohpase Cy is involved in growth factor controlled signal transduction pathways. The receptor tyrosine kinases (see Chapter 8) phosphorylate the enzyme at specific tyrosine residues and initiate activation of the enzyme. Characteristic for the structure of phospholipase Cy is the occurrence of SH2 and SH3 domains (see Chapter 8). These represent protein modules that serve to attach further partner proteins. 

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