Structural mechanism for STI-571 inhibition of Abelson tyrosine kinase
Structural mechanism for STI-571 inhibition of Abelson tyrosine kinase
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DOI：
10.1126/science.289.5486.1938
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发表时间：
2000-09-15
期刊：
影响因子：
56.9
通讯作者：
Kuriyan, J
中科院分区：
文献类型：
--
作者：
Schindler, T;Bornmann, W;Kuriyan, J
Abelson酪氨酸激酶（Abl）的无意激活可引起慢性髓性白血病（CML），一种Abl的小分子抑制剂（STI-571）可有效治疗CML。我们报道了Abl催化结构域的晶体结构，与STI-571的一个变体络合。评论：STI-571的结合是由一种非活性构象的激酶所采用的，在这种构象中，位于中心的“激活环”没有被磷酸化。该环的构象不同于活性蛋白激酶，也不同于密切相关的Src激酶的失活形式。这些结果表明，利用单个蛋白激酶的独特失活机制的化合物可以获得高亲和力和高特异性。
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. Critic:al 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.