Schindler T, Bornmann W, Pellicena P, Miller W T, Clarkson B, Kuriyan J
Laboratories of Molecular Biophysics and Howard Hughes Medical Institute, The Rockefeller University, 1230 York Avenue, New York, NY 10021, USA.
Science. 2000 Sep 15;289(5486):1938-42. doi: 10.1126/science.289.5486.1938.
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.
阿贝尔森酪氨酸激酶（Abl）的意外激活会导致慢性粒细胞白血病（CML）。一种Abl的小分子抑制剂（STI-571）对CML的治疗有效。我们报道了与STI-571变体复合的Abl催化结构域的晶体结构。STI-571结合的关键在于激酶采用非活性构象，其中位于中心的“激活环”未被磷酸化。该环的构象不同于活性蛋白激酶以及密切相关的Src激酶的非活性形式中的构象。这些结果表明，利用单个蛋白激酶独特失活机制的化合物可以实现高亲和力和高特异性。
