Kinases hinge region

Poorly soluble brickdust compounds are not preferentially selected for by HTS as is the case with greaseballs. However, brickdust compounds are extremely common in certain popular current era targets, e.g. the ATP competitive hinge region binding site in protein kinase inhibitors. 

Fig. 2. QSURF protein surface from FLO-QXP around ligand in the hinge region of the ATP binding site of a kinase. The scaffold makes two hydrogen bonds with the protein backbone (hinge). The micro-cavity on the right of the iigand dot circle) is created by three atoms in the vicinity, the iines of singuiarity in the moiecuiar surface resuits of the intersection between two protein atoms. The three color code of the protein surface corresponds to the hydrophobic area (yelloWi or negative and positive polar areas (Woe and red, respectively).

Fig. 14.1. Ribbon structure (magenta) of the phosphorylase kinase crystal structure 2PHK (20) bound with ATP (green carbons, colored by atom type) and substrate peptide (light blue ribbon). The N- and C-terminal lobes are highlighted the hinge region is shown in cyan, the a-C helix in gray, and the -loop in orange.

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.

Phosphoglycerate kinase is encoded by the mammalian X chromosome. Several mutant forms are associated with hemolytic anemia and mental disorders.885 886 Mutation of Glu 190, which is in the hinge region far from the active site, to Gin or Asn markedly reduces enzymatic activity.887... 

Fig. 2 Schematic representation of the hydrogen bonding contacts with the hinge region of the highly conserved ATP-binding site of protein kinases the natural substrate ATP (left) the organic inhibitor staurosporine (center) a metallo-pyridocarbazole scaffold (right)...

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...

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.

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