Crystal Structures of PI3Kα Complexed with PI103 and Its Derivatives: New Directions for Inhibitors Design
Crystal Structures of PI3Kα Complexed with PI103 and Its Derivatives: New Directions for Inhibitors Design
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DOI：
10.1021/ml400378e
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发表时间：
2014-02-01
影响因子：
4.2
通讯作者：
Zhang, Jian
中科院分区：
文献类型：
--
作者：
Zhao, Yanlong;Zhang, Xi;Zhang, Jian
磷脂酰肌醇 3-激酶 (PI3K) 信号通路在细胞增殖、生长和存活中发挥重要作用。过度激活的 PI3K 常见于多种人类癌症中，这证实了它是一个有希望的癌症治疗靶点。我们确定了人类 PI3K α-PI103 复合物的晶体结构，以揭示分子相互作用。根据该结构，PI103 苯酚部分 R-1 位置的取代被证明可以通过与 ATP 催化位点底部的 Lys802 形成新的氢键来提高结合亲和力。有趣的是，PI3K α-9d 复合物的晶体结构表明，Lys802 的灵活性还可以在催化位点产生额外的空间以进行进一步修饰。因此，这些晶体结构为强而特异的相互作用提供了分子基础，并证明了 Lys802 在新型 PI3K α 抑制剂设计中的重要作用。
The phosphatidylinositol 3-kinase (PI3K) signaling pathway plays important roles in cell proliferation, growth, and survival. Hyperactivated PI3K is frequently found in a wide variety of human cancers, validating it as a promising target for cancer therapy. We determined the crystal structure of the human PI3K alpha-PI103 complex to unravel molecular interactions. Based on the structure, substitution at the R-1 position of the phenol portion of PI103 was demonstrated to improve binding affinity via forming a new H-bond with Lys802 at the bottom of the ATP catalytic site. Interestingly, the crystal structure of the PI3K alpha-9d complex revealed that the flexibility of Lys802 can also induce additional space at the catalytic site for further modification. Thus, these crystal structures provide a molecular basis for the strong and specific interactions and demonstrate the important role of Lys802 in the design of novel PI3K alpha inhibitors.