Structural mechanism for STI-571 inhibition of Abelson tyrosine kinase

The inadvertent activation of the Abelson tyrosine kinase (Abl) causes chro nic myelogenous Leukemia (CML), A small-molecule inhibitor of Abl (STI-571) is effective in the treatment of CML. We report the crystal structure of t he catalytic domain of Abl, complexed to a variant of STI-571. Critic:al to the binding of STI-571 is the adoption by the kinase of an inactive confor mation, in which a centrally Located "activation Loop" is not phosphorylate d. The conformation of this Loop is distinct from that in active protein ki nases, as well as in the inactive form of the closely related Src kinases, These results suggest that compounds that exploit the distinctive inactivat ion mechanisms of individual protein kinases can achieve both high affinity and high specificity.