Chronic myelogenous leukemia (CML) occurs primarily in adults and is caused by a chromosomal translocation event that produces a persistently activated form of a protein kinase called Abl. A small molecule inhibitor of the Abl kinase, called STI-571, has shown very encouraging results in early clinical trials. To investigate how this inhibitor achieves its high specificity for Abl, Schindler et al. (see the news story by Marx) determined the crystal structure of the catalytic domain of Abl in a complex with a variant of STI-571. The ability of the drug to penetrate deeply into the core of the Abl catalytic domain appears to depend on a distinctive inactive conformation adopted by the "activation loop," a protein segment that controls enzyme activity by switching between an inactive and an active state. Because the catalytic domains of other protein kinases also adopt characteristic inactive conformations, this finding offers hope that similar inhibitors can be designed for other medically relevant protein kinases.
Schindler, T., Bornmann, W., Pellicena, P., Miller, W.T., Clarkson, B., and Kuriyan, J. (2000) Structural mechanism for STI-571 inhibition of Abelson tyrosine kinase. Science 289: 1938-1942. [Abstract] [Full Text]
Marx, J. (2000) Cancer fighter's modus operandi revealed. Science 289: 1857-1859. [Full Text]