Structural Mechanism for STI-571 Inhibition of Abelson Tyrosine Kinase
Thomas Schindler, William Bornmann, Patricia Pellicena, W. Todd Miller, Bayard
Clarkson, John Kuriyan
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
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Original Structure, with STI-571 variant lacking a solubilizing group (Schindler
et al.) PDB Code 1FPU
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Newer Structure, with intact STI-571 (Bhushan Nagar) PDB Code 1IEP
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