Walker E H, Pacold M E, Perisic O, Stephens L, Hawkins P T, Wymann M P, Williams R L
MRC Laboratory of Molecular Biology, MRC Centre, Cambridge, United Kingdom.
Mol Cell. 2000 Oct;6(4):909-19. doi: 10.1016/s1097-2765(05)00089-4.
The specific phosphoinositide 3-kinase (PI3K) inhibitors wortmannin and LY294002 have been invaluable tools for elucidating the roles of these enzymes in signal transduction pathways. The X-ray crystallographic structures of PI3Kgamma bound to these lipid kinase inhibitors and to the broad-spectrum protein kinase inhibitors quercetin, myricetin, and staurosporine reveal how these compounds fit into the ATP binding pocket. With a nanomolar IC50, wortmannin most closely fits and fills the active site and induces a conformational change in the catalytic domain. Surprisingly, LY294002 and the lead compound on which it was designed, quercetin, as well as the closely related flavonoid myricetin bind PI3K in remarkably different orientations that are related to each other by 180 degrees rotations. Staurosporine/PI3K interactions are reminiscent of low-affinity protein kinase/staurosporine complexes. These results provide a rich basis for development of isoform-specific PI3K inhibitors with therapeutic potential.
特异性磷酸肌醇3激酶（PI3K）抑制剂渥曼青霉素和LY294002是阐明这些酶在信号转导途径中作用的重要工具。与这些脂质激酶抑制剂以及广谱蛋白激酶抑制剂槲皮素、杨梅素和星形孢菌素结合的PI3Kγ的X射线晶体结构揭示了这些化合物如何契合ATP结合口袋。渥曼青霉素的半数抑制浓度（IC50）为纳摩尔级别，它与活性位点的契合度最高且能填满活性位点，并在催化结构域中诱导构象变化。令人惊讶的是，LY294002及其设计所基于的先导化合物槲皮素，以及与之密切相关的类黄酮杨梅素，以彼此相差180度旋转的显著不同方向与PI3K结合。星形孢菌素与PI3K的相互作用让人联想到低亲和力蛋白激酶/星形孢菌素复合物。这些结果为开发具有治疗潜力的亚型特异性PI3K抑制剂提供了丰富的基础。
