Structural Mechanism for STI-571 Inhibition of Abelson Tyrosine Kinase

Thomas Schindler, William Bornmann, Patricia Pellicena, W. Todd Miller, Bayard Clarkson, John Kuriyan

Science Schindler et al. 289 (5486): 2000.

The inadvertent activation of the Abelson tyrosine kinase (Abl) causes chronic myelogenous leukemia (CML). A small molecule inhibitor of Abl (STI-571, Gleevec, Novartis) is effective in the treatment of CML. We report the crystal structure of the catalytic domain of Abl, complexed to a variant of STI-571. Critical to the binding of STI-571 is the adoption by the kinase of an inactive conformation, in which a centrally located "activation loop" is not phosphorylated. The conformation of this loop is distinct from that in active protein kinases, as well as in the inactive form of the closely related Src kinases. These results suggest that compounds that exploit the distinctive inactivation mechanisms of individual protein kinases can achieve both high affinity and high specificity.

Protein Structure Coordinates

- Original Structure, with STI-571 variant lacking a solubilizing group (Schindler et al.) PDB Code 1FPU

- Newer Structure, with intact STI-571 (Bhushan Nagar) PDB Code 1IEP

Images (Click on the small image to get a large one:

Animation of STI-571:Abl Complex (Copyright 2000, John Kuriyan)