CRYSTALLOGRAPHIC STUDIES OF VIRAL CYCLINS AND CDK6

近年来，调节细胞周期进程的关键酶已经被发现， 被广泛地识别和表征。 的重大转变 真核细胞周期由细胞周期蛋白依赖性蛋白控制 通过磷酸化发挥其调节功能的激酶（CDKs） 参与细胞周期转变的关键蛋白质。 以确保适当 细胞周期事件的时间和协调，CDK激酶活性是 受到各种机制的严格控制，例如激活 脱辅基酶通过与细胞周期蛋白形成复合物，激活和抑制 磷酸化和与抑制蛋白的复合物形成。 不 令人惊讶的是，它们在细胞周期控制、突变和 已经报道细胞周期蛋白和CDK的过表达是致癌的 事件 最近发现的两种致癌性疱疹蛋白 与人D型细胞周期蛋白显示出密切同源性的病毒支持 这些观察。 来自松鼠猴疱疹病毒（HVS）的V-细胞周期蛋白和k- 来自卡波西肉瘤相关疱疹病毒（KSHV）的细胞周期蛋白显示24 与人细胞周期蛋白D1和D3的同源性分别为10%和31%， 分别 它们与CDK 4和CDK 6缔合，导致强的 对视网膜母细胞瘤蛋白和组蛋白H1的激酶活性。 这种高 未经许可的激酶活性水平最可能诱导 HVS和KSHV疾病固有的细胞增殖。 序列 病毒细胞周期蛋白与D型细胞周期蛋白的同源性及其相似性 在CDK活化中使病毒周期蛋白成为研究活化的良好系统 CDK 4和CDK 6的机制，如果没有，可能导致致癌事件 适当控制。此外，KSHV与开发 尤其是艾滋病患者 因此，研究 两个同源的病毒细胞周期蛋白可能有助于理解 发病机制和治疗。 短期目标是确定 v-cyclin。 长期目标是确定k- 细胞周期蛋白和CDK 6的X射线晶体学研究CDK 6的复合物 与病毒细胞周期蛋白的最终目的是结构确定， 好. 这些信息将有助于理解激活机制 引起各种疾病的病毒蛋白质对宿主细胞CDKs的作用 包括癌症

In recent years, key enzymes that regulate cell cycle progression have been identified and characterized extensively. The major transition of the eucaryotic cell cycle are controlled by cyclin-dependent protein kinases (CDKs) that exert their regulatory function by phosphorylation of key proteins involved in cell cycle transitions. To ensure proper timing and coordination of cell cycle events, CDK kinase activity is tightly controlled by various mechanisms, such as activation of the apoenzyme by complex formation with cyclins, activating and inhibiting phosphorylations, and complex formation with inhibitory proteins. Not surprisingly from their key role in cell cycle control, mutations and overexpression of cyclins and CDKs have been reported to be oncogenic events. The recent discovery of two proteins from oncogenic herpes viruses that show close homology with human D-type cyclins supports these observations. V-cyclin from herpesvirus saimiri (HVS) and k- cyclin from Kaposi's sarcoma associated herpesvirus (KSHV) show 24 percent and 31 percent identity with human cyclin D1 and D3, respectively. They associate with CDK4 and CDK6, resulting in strong kinase activity toward retinoblastoma protein and histone H1. This high level of unlicensed kinase activity most likely induces deregulation of cell proliferation inherent to HVS and KSHV diseases. The sequence homologies between viral cyclins and D-type cyclins and the similarities in CDK activation make viral cyclins a good system to study activation mechanisms of CDK4 and CDK6, that might lead to oncogenic events if not properly controlled. Futhermore, KSHV is implicated in the development of Kaposi's sarcoma, especially in AIDS patients. Hence, studies of the two homologous viral cylclins may contribute to understanding the pathogenesis and treatment of this disease. The short term goal is to determine the three-dimensional structure of v-cyclin. The long-term goal is to determine the structures of k- cyclin, and CDK6 by x-ray crystallography and to study complexes of CDK6 with viral cyclins with the final aim of structure determination as well. This information will help to understand the activation mechanism of host cell CDKs by proteins from viruses that cause various diseases including cancer.