Structural determinants of phosphoinositide 3-kinase inhibition by wortmannin, LY294002, quercetin, myricetin, and staurosporine
Structural determinants of phosphoinositide 3-kinase inhibition by wortmannin, LY294002, quercetin, myricetin, and staurosporine
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DOI：
10.1016/s1097-2765(05)00089-4
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发表时间：
2000-10-01
期刊：
影响因子：
16
通讯作者：
Williams, RL
中科院分区：
文献类型：
--
作者：
Walker, EH;Pacold, ME;Williams, RL
特异性磷酸肌肽3-激酶（PI3K）抑制剂wortmannin和LY294002已经成为阐明这些酶在信号转导途径中的作用的宝贵工具。结合这些脂质激酶抑制剂和广谱蛋白激酶抑制剂槲皮素、杨梅素和星孢素的PI3K γ的x射线晶体结构揭示了这些化合物是如何融入ATP结合口袋的。wortmannin具有纳摩尔的IC50，最紧密地贴合并填充活性位点，并在催化域中引起构象变化。令人惊讶的是，LY294002和其设计的先导化合物槲皮素，以及密切相关的类黄酮杨梅素结合PI3K的方向明显不同，彼此以180度旋转相关。Staurosporine/PI3K相互作用让人想起低亲和力的蛋白激酶/ stausporine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。
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 PI3K gamma 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.