Gleevec(STI-571)抑制Bcr-Abl酪氨酸激酶的机理  

Structural Mechanism for Gleevec(STI-571) Inhibition of Bcr-AbI Tyrosine Kinase

作　　者：于海侠[1] 

机构地区：[1]吉林工业职业技术学院应用化工系,吉林市132013

出　　处：《技术与教育》2010年第2期5-7,共3页Technique & Education

摘　　要：Bcr-Abl酪氨酸激酶失活导致慢性粒细胞白血病(CML)。Bcr-Abl小分子抑制剂Gleevec(STI-571)能有效治疗CML,它是利用Gleevec(STI-571)的变构来缔合Abl的催化区域的晶体结构即激酶的非活性构象,Gleevec(STI-571)键合在非磷酸化的活性环上。这个环的构象区别于活性蛋白激酶的构象,也区别于与Abl密切相关的Src激酶的非活性形态。这些结果表明:化合物利用个别蛋白激酶独特的非活性机理能获得高亲和力和特异性。The inadvertent activation of Bcr-Abl tyrosine kinase causes chronic myelogenous leukemia (CML).A small-molecule inhibitor of Bcr-Abl[Gleevec(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 Gleevec(STI-571). Critical to the binding of Gleevec(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.

关 键 词：BCR-ABL 非活性构象 Gleevec(STI-571) 

分 类 号：R733.7[医药卫生—肿瘤]