Schindler T, Sicheri F, Pico A, Gazit A, Levitzki A, Kuriyan J
Laboratories of Molecular Biophysics, Rockefeller University, New York, New York 10021, USA.
Mol Cell. 1999 May;3(5):639-48. doi: 10.1016/s1097-2765(00)80357-3.
The crystal structure of the autoinhibited form of Hck has been determined at 2.0 A resolution, in complex with a specific pyrazolo pyrimidine-type inhibitor, PP1. The activation segment, a key regulatory component of the catalytic domain, is unphosphorylated and is visualized in its entirety. Tyr-416, the site of activating autophosphorylation in the Src family kinases, is positioned such that access to the catalytic machinery is blocked. PP1 is bound at the ATP-binding site of the kinase, and a methylphenyl group on PP1 is inserted into an adjacent hydrophobic pocket. The enlargement of this pocket in autoinhibited Src kinases suggests a route toward the development of inhibitors that are specific for the inactive forms of these proteins.
已在2.0埃分辨率下确定了与特定吡唑并嘧啶类抑制剂PP1复合的Hck自抑制形式的晶体结构。激活片段是催化结构域的关键调节成分，未磷酸化且整体可见。Src家族激酶中激活自磷酸化的位点Tyr-416的位置使得催化机制无法接近。PP1结合在激酶的ATP结合位点，PP1上的甲基苯基插入相邻的疏水口袋。自抑制Src激酶中这个口袋的扩大为开发针对这些蛋白质无活性形式的特异性抑制剂指明了一条途径。
