BTB-1: A Small Molecule Inhibitor of the Mitotic Motor Protein Kif18A
BTB-1: A Small Molecule Inhibitor of the Mitotic Motor Protein Kif18A
复制标题
DOI：
10.1002/anie.200904510
复制
发表时间：
2009-01-01
影响因子：
16.6
通讯作者：
Mayer, Thomas U.
中科院分区：
文献类型：
--
作者：
Catarinella, Mario;Gruener, Tamara;Mayer, Thomas U.
每种生物的生存和发展都依赖于细胞分裂过程中基因组的平均分配。这个过程中的错误可能导致人类严重的发育缺陷和癌症。基因组精确分布的关键是由动态微管（Mts）组成的有丝分裂纺锤体。[1]有丝分裂纺锤体的形状和功能取决于各种驱动蛋白的协同作用，这些驱动蛋白是分子马达蛋白，它们作为微管刺激的ATP酶将化学能转化为机械力。最近，我们确定了驱动蛋白-8成员Kif 18 A作为在纺锤体赤道染色体的正确对齐的中心组件。[2]此外，体外分析表明，Kif 18 A区别于所有其他驱动蛋白的双重功能：运动性和解聚酶活性。[2 4]由于其快速且通常可逆的作用模式，小分子非常适合剖析蛋白质的功能和机制。鉴于Kif 18 A的复杂酶特性，我们建立了一个小分子筛选来鉴定Kif 18 A的抑制剂。在本文中，我们报告了BTB-1的发现（图1a），这是Kif 18 A的第一个小分子抑制剂。我们发现BTB-1有效抑制Kif 18 A的ATP酶活性（IC 50 = 1.69 mm），但不抑制其他测试的关键有丝分裂驱动蛋白。BTB-1以可逆的方式阻断Kif 18 A的运动性。值得注意的是，BTB-1以三磷酸腺苷（ATP）竞争性但微管非竞争性的方式抑制Kif 18 A，并减缓细胞通过有丝分裂的进程。
The survival and development of each organism relies on the equal partitioning of its genome during cell division. Errors in this process can lead to severe developmental defects and cancer in humans. Key for the accurate distribution of the genome is the mitotic spindle composed of dynamic microtubules (Mts).[1] The shape and function of the mitotic spindle depends on the concerted action of various kinesins, these are molecular motor proteins which as microtubule-stimulated ATPases convert chemical energy into mechanical force. Recently, we identified the kinesin-8 member Kif18A as a central component for the correct alignment of chromosomes at the spindle equator.[2] Furthermore, in vitro analyses revealed that Kif18A distinguishes itself from all other kinesins by its dual functionality: motility and depolymerase activity.[2 4] Owing to their fast and often reversible mode of action, small molecules are ideally suited to dissect the function and mechanism of proteins. Given the complex enzymatic characteristics of Kif18A, we set up a smallmolecule screen to identify inhibitors of Kif18A. Herein we report the discovery of BTB-1 (Figure 1a), the first smallmolecule inhibitor of Kif18A. We show that BTB-1 potently inhibits the ATPase activity of Kif18A (IC50= 1.69 mm) but not of other tested key mitotic kinesins. BTB-1 blocks the motility of Kif18A in a reversible manner. Notably, BTB-1 inhibits Kif18A in an adenosine triphosphate (ATP)-competitive but microtubule-uncompetitive manner and slows down the progression of cells through mitosis.