Biochemistry

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Science  25 May 2012:
Vol. 336, Issue 6084, pp. 961-962
DOI: 10.1126/science.336.6084.961-d

Protein kinases that function in signaling pathways controlling cell growth and survival are potential drug targets for fighting cancer and other diseases. Predicting the actions of kinase inhibitors in cells, especially cancer cells, is difficult, however, without a detailed understanding of the normal regulation of the target enzymes. Lin et al. provide insight into how the kinase Akt reacts to inhibitors that compete with adenosine triphosphate (ATP) for binding to the active site. ATP-competitive inhibitors actually increase the phosphorylation of Akt at its activating sites. This is because in the ATP-bound (but not ADP-bound) conformation, the activating phosphorylation sites are inaccessible to phosphatases that can dephopshorylate them. Thus, when activated and bound to ATP, the enzyme is resistant to inactivation until it has catalyzed one round of phosphor ylation, at which point it becomes susceptible to inactivating phosphatases. Furthermore, the ATP-competitive inhibitor studied bound preferentially to the active form of Akt, leading the authors to propose that it might preferentially target tumor cells where Akt is highly activated, with fewer (potentially deleterious) effects on normal cells.

Sci. Signal. 5, ra37 (2012).

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