Hinge domain, kinases

Adenine-binding region (ABR) - all ATP-competitive kinase inhibitors bind in this hydrophobic region and interact with the hinge domain via hydrogen bonds. 

Fig. 16.2. Cell cycle, Chkl at the G2/M checkpoint, and key structural features of the Chkl kinase domain (4a). The highlighted location is the hinge region of the Chkl kinase domain, which also corresponds to the same regions of protein-ligand structures shown in Fig. 16.1.

Figure 6.3 Schematic illustration of the generation of inhibitor-insensitive kinase mutants. The interaction of ATP-site competitors with kinase domains has been structurally characterized through the so-called Traxler model [10]. The part of the inhibitor that corresponds to the adenine ring binds to the hinge region of the kinase domain via H bonds. Next to the hinge region are the hydrophobic back pocket and the surface-exposed front pocket, which do not play a role in ATP binding. However, these pockets are extremely critical determinants in inhibitor binding, since the...

A physical technique for the study of conformation based on measuring changes in heat capacity of a molecule under various conditions. See Zecchinon, L., Oriol, A., Netzel, U. et al.. Stability domains, substrate-induced conformational changes, and hinge-bending motions in a psychro-philic phosphoglycerate kinase. A microcalorimetric study, J. Biol. Chem. 280, 41307-41314, 2005. 

Figure 6.11. Pharmacophore derived based on the interactions between human cyclin-dependent kinase 2 and the adenine-derived inhibitor H717 as observed in the X-ray structure of the complex (PDB entry 1G5S). Dashed lines highlight hydrogen-bonding interactions. HBD, hydrogen-bond donor HBA, hydrogen-bond acceptor. The hinge region is linking the, N- and C-terminal domains of a kinase.

The core of all eukaryotic Ser/Thr- and Tyr-specific protein kinases adopt a common fold illustrated in Fig. 7.3 for the tyrosine kinase domain of the insulin receptor. The structure comprises two lobes that are conneded by a hinge region. The N-terminal lobe contains five / -structures and one a-helix, named C-helix. In contrast, the larger C-terminal lobe is mostly a-helical. It comprises a four-helix bundle, additional a-he-lices, and two short yS-strands. ATP and 1 or 2 metal ions are bound at the interface of the two lobes, while the binding site for the peptide substrate is located mostly in the C-terminal lobe. The following structural elements have been found to be critical for catalysis and for protein kinase control ... 

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 ... 

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