Richards Mark W, O'Regan Laura, Mas-Droux Corine, Blot Joelle M Y, Cheung Jack, Hoelder Swen, Fry Andrew M, Bayliss Richard
Institute of Cancer Research, London, UK.
Mol Cell. 2009 Nov 25;36(4):560-70. doi: 10.1016/j.molcel.2009.09.038.
Mitosis is controlled by multiple protein kinases, many of which are abnormally expressed in human cancers. Nek2, Nek6, Nek7, and Nek9 are NIMA-related kinases essential for proper mitotic progression. We determined the atomic structure of Nek7 and discovered an autoinhibited conformation that suggests a regulatory mechanism not previously described in kinases. Additionally, Nek2 adopts the same conformation when bound to a drug-like molecule. In both structures, a tyrosine side chain points into the active site, interacts with the activation loop, and blocks the alphaC helix. Tyrosine mutants of Nek7 and the related kinase Nek6 are constitutively active. The activity of Nek6 and Nek7, but not the tyrosine mutant, is increased by interaction with the Nek9 noncatalytic C-terminal domain, suggesting a mechanism in which the tyrosine is released from its autoinhibitory position. The autoinhibitory conformation is common to three Neks and provides a potential target for selective kinase inhibitors.
有丝分裂受多种蛋白激酶控制，其中许多在人类癌症中异常表达。Nek2、Nek6、Nek7和Nek9是与NIMA相关的激酶，对有丝分裂的正常进行至关重要。我们确定了Nek7的原子结构，并发现了一种自身抑制构象，这表明了一种激酶中以前未描述的调节机制。此外，Nek2与一种类药物分子结合时采用相同的构象。在这两种结构中，一个酪氨酸侧链指向活性位点，与激活环相互作用，并阻断αC螺旋。Nek7和相关激酶Nek6的酪氨酸突变体具有组成型活性。Nek6和Nek7（而非酪氨酸突变体）与Nek9非催化性C末端结构域相互作用后活性增加，这表明存在一种机制，酪氨酸从其自身抑制位置释放。这种自身抑制构象在三种Nek蛋白中很常见，并为选择性激酶抑制剂提供了一个潜在靶点。
