Crystal structure of a viral cyclin, a positive regulator of cyclin-dependent kinase 6.
Crystal structure of a viral cyclin, a positive regulator of cyclin-dependent kinase 6.
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病毒细胞周期蛋白的晶体结构，细胞周期蛋白依赖性激酶 6 的正调节因子。
DOI：
10.1016/s0969-2126(99)80035-5
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发表时间：
1999
期刊：
影响因子：
--
通讯作者：
Kim,SH
中科院分区：
文献类型：
--
作者：
Schulze-Gahmen,U;Jung,JU;Kim,SH
背景：细胞周期蛋白依赖性激酶（CDKs）在细胞周期调控中起重要作用，通过与细胞周期蛋白形成复合物和磷酸化激活。细胞周期蛋白和细胞周期蛋白依赖性激酶的过度表达和突变与肿瘤的发生和发展有关。疱疹病毒saimiri编码的细胞周期蛋白（v-cyclin）与D型细胞周期蛋白具有高度的序列同源性，并能特异性地激活宿主细胞的CDK 6。核心结构域的结构与来自人类细胞的细胞周期蛋白A和细胞周期蛋白H的结构非常相似。为了理解v-细胞周期蛋白对CDK 6的特异性的结构基础以及复合物对p21和INK 4家族的抑制剂的不敏感性，基于与CDK 2和CDK抑制剂p27 Kip 1复合的人细胞周期蛋白A的已知结构，建立了v-细胞周期蛋白-CDK 2模型。尽管细胞周期蛋白A和CDK 2之间的许多关键相互作用在v-细胞周期蛋白-CDK 2复合物中是保守的，一些由于骨架构象的变化或侧链差异而在空间或静电上表现出不利的，并且可能有助于CDK 6的v-细胞周期蛋白选择性。v-细胞周期蛋白-CDK 6复合物对p21家族抑制剂的不敏感性可能是由于v-细胞周期蛋白的结构变化导致更平坦的表面积，从而提供与蛋白质抑制剂更少的潜在接触。此外，v-细胞周期蛋白的序列变化消除了p27 Kip 1抑制剂原子的氢键伙伴。这种结构为v-细胞周期蛋白和宿主细胞周期蛋白之间的相互作用提供了第一个模型;这些相互作用对于病毒存活以及宿主细胞的致癌转化可能是重要的。
Background:Cyclin-dependent kinases (CDKs) have a central role in cell-cycle control and are activated by complex formation with positive regulatory proteins called cyclins and by phosphorylation. The overexpression and mutation of cyclins and CDKs has been associated with tumorigenesis and oncogenesis. A virus-encoded cyclin (v-cyclin) from herpesvirus saimiri has been shown to exhibit highest sequence homology to type D cyclins and specifically activates CDK6 of host cells to a very high degree.Results:We have determined the first X-ray structure of a v-cyclin to 3.0 Å resolution. The structure of the core domains is very similar to those of cyclin A and cyclin H from human cells. To understand the structural basis for the v-cyclin specificity for CDK6 and the insensitivity of the complex to inhibitors of the p21 and INK4 families, a v-cyclin–CDK2 model was built on the basis of the known structures of human cyclin A in complex with CDK2 and the CDK inhibitor p27Kip1.Conclusions:Although many critical interactions between cyclin A and CDK2 would be conserved in a v-cyclin–CDK2 complex, some appear sterically or electrostatically unfavorable due to shifts in the backbone conformation or sidechain differences and may contribute to v-cyclin selectivity for CDK6. The insensitivity of v-cyclin–CDK6 complexes to inhibitors of the p21 family is probably due to structural changes in v-cyclin that lead to a flatter surface area offering fewer potential contacts with the protein inhibitor. In addition, sequence changes in v-cyclin eliminate hydrogen-bonding partners for atoms of the p27Kip1inhibitor. This structure provides the first model for interactions between v-cyclins and host cell-cycle proteins; these interactions may be important for virus survival as well as oncogenic transformation of host cells.