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首页> 外文期刊>Nature >Structural basis for inhibition of the cyclin-dependent kinase Cdk6 by the tumour suppressor p16INK4a.
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Structural basis for inhibition of the cyclin-dependent kinase Cdk6 by the tumour suppressor p16INK4a.

机译：肿瘤抑制因子p16INK4a抑制细胞周期蛋白依赖性激酶Cdk6的结构基础。

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摘要

The cyclin-dependent kinases 4 and 6 (Cdk4/6) that control the G1 phase of the cell cycle and their inhibitor, the p16INK4a tumour suppressor, have a central role in cell proliferation and in tumorigenesis. The structures of Cdk6 bound to p16INK4a and to the related p19INK4d reveal that the INK4 inhibitors bind next to the ATP-binding site of the catalytic cleft, opposite where the activating cyclin subunit binds. They prevent cyclin binding indirectly by causing structural changes that propagate to the cyclin-binding site. The INK4 inhibitors also distort the kinase catalytic cleft and interfere with ATP binding, which explains how they can inhibit the preassembled Cdk4/6-cyclin D complexes as well. Tumour-derived mutations in INK4a and Cdk4 map to interface contacts, solidifying the role of CDK binding and inhibition in the tumour suppressor activity of p16INK4a.
机译：控制细胞周期G1期的细胞周期蛋白依赖性激酶4和6（Cdk4 / 6）及其抑制剂p16INK4a肿瘤抑制剂在细胞增殖和肿瘤发生中起着核心作用。与p16INK4a和相关的p19INK4d结合的Cdk6的结构表明，INK4抑制剂紧接着催化裂隙的ATP结合位点结合，而激活的细胞周期蛋白亚基则与之结合。它们通过引起传播到细胞周期蛋白结合位点的结构改变来间接防止细胞周期蛋白结合。 INK4抑制剂还扭曲了激酶的催化裂隙，并干扰了ATP的结合，这说明了它们也可以抑制预组装的Cdk4 / 6-cyclin D复合物。 INK4a和Cdk4中源自肿瘤的突变映射到界面接触，巩固了CDK结合和抑制作用在p16INK4a的肿瘤抑制活性中的作用。

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