Protein kinases characterizing kinase-ligand

We have previously calculated conformational free energy differences for a well-suited model system, the catalytic subunit of cAMP-dependent protein kinase (cAPK), which is the best characterized member of the protein kinase family. It has been crystallized in three different conformations and our main focus was on how ligand binding shifts the equilibrium among these ([Helms and McCammon 1997]). As an example using state-of-the-art computational techniques, we summarize the main conclusions of this study and discuss a variety of methods that may be used to extend this study into the dynamic regime of protein domain motion. 

It is thus necessary to confirm the existence of modified cellular function following ligand-receptor or drug-enzyme interaction. Such in vitro experiments, performed on isolated cells, either native or transfected with the protein of interest, can be undertaken for mechanistic and/or therapeutic purposes. The data depicted in Figure 3.10 illustrate the fact that, in HEK293 cells in culture, inhibition of the enzyme glycogen synthetase kinase 3(3 (GSK-3(3) decreases tan protein hyperphosphorylation, one of the anatomopathological hallmarks of Alzheimer s disease, and may thus represent a potential therapeutic approach for this disease. Alternatively, this experimental set-up can also be used for mechanistic purposes to characterize the efficacy of compounds as GSK-3 3 inhibitors. When compared to simple in vitro experiments in which the activity of the purified enzyme is measured in the presence of a... 

Many protein-ligand complexes are characterized by the presence of both polar and lipophilic interactions. The bound conformation of the ligand is determined by the relative importance of these contributions. An interesting example highlighting several important aspects was recenfly described by Lange and co-workers using the binding of non-peptidic inhibitors to the SH2 domain of src kinase [28]. The inhibitors are essentially tetrapeptide mimetics with tyrosine-phosphate or a... 

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