Kinase, kinases structural aspects

Engh, Richard A. and Bossemeyer, D. (2002) Structural aspects of protein kinase control—role of conformational flexibility. Pharmacol. Therapeut. 93, 99-111. 

Fig. 8.12B. Structure of c-Src kinase phosphorylated at Tyrosine 527. Ribbon diagram showing the structure and organization of the closed conformation" of c-Src kinase. Two aspects of the structure are important for the regulation of c-Src kinase i) The phosphorylated Tyr 527 of the C-terminal tail is engaged in an intramolecular interaction with the SH2 domain, ii) The SH3 domain binds to the linker between the SH2 domain and the kinase domain. Both interactions are assumed to fix an inactive state of the kinase.

One of the most challenging aspects of obtaining a kinase crystal structure is designing the initial constructs. Recent advances in high-throughput cloning techniques, affinity purification tags and crystallization robots have however allowed for multiple constructs to be tested rapidly in parallel. 

This class of receptors transmits signals carried by hormones and growth factors. The structure consists of an extracellular domain for binding ligands and a cytoplasmic enzyme domain. The function of kinases is to enable phosphorylation. Phosphorylation regulates most aspects of cell life. 

General aspects of enzymatic reactions cateuLyzed by kinases are briefly mentioned. Many alternate substrates, competitive inhibitors and affinity labels based either on the structure of ATP or on the structure of the non-ATP kinase substrates are described. Several examples are presented that should be of particular interest to the medicinal chemist. Finally, the design of an affinity label for creatine kinase is reviewed as an example of how such information can be used in the search for agents directed at an enzyme s active site. 

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