Chapter 68 - Structures of Serine/Threonine and Tyrosine Kinases

Abstract

The structures of Ser/Thr and tyrosine kinases are strikingly similar when these enzymes are released from inhibitory interactions. In contrast, the mechanisms by which kinases are inhibited are numerous, and these distinctregulatory mechanisms result in quite different conformations for the inactive states of kinases. The unexpected diversity in the structures of inactive kinases provides routes to the acquisition of specificity by small-molecule inhibitorsof kinase function. Eukaryotic protein kinases that phosphorylate serine/threonine or tyrosine residues constitute a large family of enzymes that are critical components of cell signaling and regulatory pathways. The nature of the amino acid that is phosphorylated defines the two major classes of protein kinases in eukaryotic cells: serine/threonine (Ser/Thr) kinases and tyrosine (Tyr) kinases. Despite the differences in their substrate specificities, Ser/Thr and tyrosine kinases are very closely related in terms of the structure of their catalytic domains. Ser/Thr kinases are found in all eukaryotes and function in a broad range of signaling pathways, including those that control transcription or the regulation of metabolic pathways. Tyrosine kinases are a later evolutionary offshoot of the family and are predominantly found in multicellular animals, where they play important roles in intercellular signaling.