Abstract：
Cell cycle transitions are controlled by multiple cell cycle regulators, especially CDKs. Several CDKs, including CDK1-4 and CDK6, promote cell cycle progression directly. Among them, CDK3 is critically important because it triggers the transitions of G0 to G1 and G1 to S phase through binding to cyclin C and cyclin E1, respectively. In contrast to its highly related homologs, the molecular basis of CDK3 activation remains elusive due to the lack of structural information of CDK3, particularly in cyclin bound form. Here we report the crystal structure of CDK3 in complex with cyclin E1 at 2.25 Å resolution. CDK3 resembles CDK2 in that both adopt a similar fold and bind cyclin E1 in a similar way. The structural discrepancy between CDK3 and CDK2 may reflect their substrate specificity. Profiling a panel of CDK inhibitors reveals that dinaciclib inhibits CDK3-cyclin E1 potently and specifically. The structure of CDK3-cyclin E1 bound to dinaciclib reveals the inhibitory mechanism. The structural and biochemical results uncover the mechanism of CDK3 activation by cyclin E1 and lays a foundation for structural-based drug design.
摘要：
细胞周期转换受多个细胞周期调节因子控制,尤其是CDKs.几个CDK，包括CDK1-4和CDK6，直接促进细胞周期进程。其中,CDK3至关重要，因为它通过分别与细胞周期蛋白C和细胞周期蛋白E1结合而触发G0至G1和G1至S期的转变。与其高度相关的同源物相反，由于缺乏CDK3的结构信息，特别是在细胞周期蛋白结合形式中，CDK3活化的分子基础仍然难以捉摸。在这里，我们以2.25µ分辨率报告了CDK3与细胞周期蛋白E1的复合物的晶体结构。CDK3类似于CDK2,因为两者采用相似的折叠并且以相似的方式结合细胞周期蛋白E1。CDK3和CDK2之间的结构差异可能反映了它们的底物特异性。分析一组CDK抑制剂显示dinaciclib有效且特异性地抑制CDK3-cyclinE1。与dinaciclib结合的CDK3-cyclinE1的结构揭示了抑制机制。结构和生化结果揭示了cyclinE1激活CDK3的机制，为基于结构的药物设计奠定了基础。
