Protein kinase Structure

Johnson, L.N., Noble, M.E.M., Owen, D.J. Active and inactive protein kinases structural basis for regulation. 

The catalytic domain of protein kinase A has a two lobe structure, composed of a smaller lobe with a large portion of P-sheet structures and a larger lobe that is mostly a-helical. All Ser/Thr- and Tyr-specific protein kinases structurally characterized to date show a similar domain structure. 

Fig. 8.7. Structure of the catalytic domain of the insulin receptor. The crystal structure of the tyrosine kinase domain of the insulin receptor (Hubbard et al., 1994) has a two-lobe structure that is very similar to the structure of the Ser/Thr-specific protein kinases. Structural elements of catalytic and regulatory importance are shown. The P loop mediates binding of the phosphate residue of ATP the catalytic loop contains a catalytically essential Asp and Asn residue, found in equivalent positions as conserved residues in many Ser/Thr-specific and Tyr-specific protein kinases. Access to the active center is blocked by a regulatory loop containing three Tyr residues (Tyrll58, Tyrll62 and Tyrll63). Tyrll62 undergoes autophosphorylation in the course of activation of the insulin receptor. MOLSKRIPT representation according to Kraulis, (1991).

Johnson, L. N. (1996). Active and inactive protein kinases Structural basis for regulation. Cell 85, 149-158. 

Classifying protein kinase structures guides use of ligand-selectivity profiles to predict inactive conformations structure of lck/imatinib complex. Proteins 70, 1451-1460. 

Overall, the protein kinase structures contain several flexible elements that can be fixed in either an active or an inactive conformation. The flexible hinge between the two lobes allows for their regulated movement. Other highly mobile elements are the activation segment and, to a lesser extent, the C-helix. The structural information on the active state of several protein kinases shows a very similar structure of the catalytic domain. The following structural features are characteristic of the activated state of protein kinases ... 

Whereas fully active protein kinases appear to adopt a similar active conformation, the inactive states of protein kinases are very diverse. There are many ways to fix the flexible protein kinase structure in an inactive state. Overall, the inactive states are characterized by a more open conformation of the two lobes, precluding optimal orientation of residues involved in substrate binding and catalysis. The cell uses the following mechanisms for fixation of inactive protein kinase states (Fig.7.5) ... 

Fig. 13.8 Active and inactive Cyclin-dependent protein kinase structures. The structures shown correspond to non-activated (monomeric CDK2), partially active (CDK2-cyclinA complex), fully activated (Thrl60-phosphorylated CDK2-cyclinA complex) inhibited (p27-CDK2-cyclinA complex) and non-activatable (pl6-CDK6) complex) states. In the monomeric CDK2 and cyclinA-bound structures, the PSTAIRE helix is highlighted in red and the T loop in yellow. In the phosphorylated CDK2-cyclinA complex, the T-loop is in yellow and the phosphate group is indicated by a yellow sphere. Where present, ATP is shown in ball-and stick-representation. From Pavletich (1999), with permission.

Taylor, S. S., and E. Radzio-Andzelm. 1994. Three protein kinase structures define a common motif. Structure 2 345-355. 

Bossemeyer, D. Protein kinases - structure and fimction. FEBS Lett., 369, 57-61 (1995)... 

Zhu, L., Chen, L., Zhou, X.M., et al. (2011) Structural insights into the architecture and allostery of full-length AMP-activated protein kinase. Structure, 19 (4), 515-522. 

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