Protein kinases kinase-ligand interactions

Figure 1. Simplified schematic of receptor-mediated signal transduction in neutrophils. Binding of ligand to the receptor activates a guanine-nucleotide-binding protein (G protein), which then stimulates phospholipase C. Phosphatidylinositol 4,5-bis-phosphate is cleaved to produce diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3). DAG stimulates protein kinase C. IP3 causes the release of Ca from intracellular stores, which results in an increase in the cytosolic Ca concentration. This increase in Ca may stimulate protein kinase C, calmodulin-dependent protein kinases, and phospholipase A2. Protein phosphorylation events are thought to be important in stimulating degranulation and oxidant production. In addition, ionic fluxes occur across the plasma membrane. It is possible that phospholipase A2 and ionic channels may be governed by G protein interactions. ...

The abundance of structural information has led to a significant increase in the use of structure-based methods both to identify and to optimise inhibitors of protein kinases. The focus to date has centred upon small molecule ATP-competitive inhibitors and there are numerous examples of protein-ligand complexes available to guide design strategies. ATP binds in the cleft formed between the N- and C-terminal lobes of the protein kinase, forming several key interactions conserved across the protein kinase family. The adenine moiety lies in a hydrophobic region between the jS-sheet structure of subdomains I and II and residues from subdomains V and VIb. A... 

Bouaboula M, Perrachon S, Milligan L, Canat X, Rinaldi-Carmona M, Portier M, Barth F, Calandra B, Pecceu F, Lupker J, Maffrand JP, Le Fur G, Casellas P. A selective inverse agonist for central cannabinoid receptor inhibits mitogen-activated protein kinase activation stimulated by insulin or insulin-like growth factor 1. Evidence for a new model of receptor/ligand interactions. J Biol Chem 1997 272 22330-22339. 

Sugimoto T, Itagaki K, Irie K (2008) Design and physicochemical properties of new fluorescent ligands of protein kinase C isozymes focused on CH/7t interaction. Bioorg Med Chem 16 650-657... 

Other kinase receptors are serine/threonine kinases, protein kinases, and mitogen-activated protein (MAP) kinases. Insulin, transforming growth factor-beta (TGF- 8), and platelet-derived growth factor (PDGF) are the natural ligands that interact with kinase receptors. 

An example of the use of NMR to design inhibitors of the protein kinase p38 is shown below. The first NMR spectrum shows the resonance peaks of nicotinic acid (a) and 2-phenoxy benzoic acid (b) in the absence of a target enzyme. When a target enzyme is added, in this case the p38 MAP kinase, binding of the ligand and the enzyme causes line broadening and attenuation of the resonance peaks. This is shown by the second NMR spectrum, in which the affected peaks are those of the 2-phenoxy benzoic acid (from 7.2 ppm to 6.6 ppm), indicating the interactions between p38 MAP kinase and 2-phenoxy benzoic acid. 

Protein interior, water exclusion from, HYDROPHOBIC EFFECT PROTEIN KINASE PROTEIN KINASE 0 Protein-ligand interactions,... 

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