Structural Mechanism for STI-571 Inhibition of Abelson Tyrosine Kinase

TLDR

Activation of the Abelson tyrosine kinase (Abl) drives chronic myelogenous leukemia, and the small‑molecule inhibitor STI‑571 is an effective treatment, with Abl’s activation loop adopting a distinct conformation from both active kinases and the inactive form of related Src kinases. The study aims to determine the crystal structure of Abl’s catalytic domain bound to a STI‑571 variant. The authors solved the crystal structure of Abl’s catalytic domain in complex with a STI‑571 variant. STI‑571 binds only when Abl adopts an inactive conformation with an unphosphorylated activation loop, indicating that targeting unique inactivation mechanisms can yield high‑affinity, highly specific inhibitors.

Abstract

The inadvertent activation of the Abelson tyrosine kinase (Abl) causes chronic myelogenous leukemia (CML). A small-molecule inhibitor of Abl (STI-571) 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.