Russo A A, Tong L, Lee J O, Jeffrey P D, Pavletich N P
Cellular Biochemistry and Biophysics Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Nature. 1998 Sep 17;395(6699):237-43. doi: 10.1038/26155.
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.
细胞周期蛋白依赖性激酶4和6（Cdk4/6）控制细胞周期的G1期，其抑制剂p16INK4a肿瘤抑制因子在细胞增殖和肿瘤发生中起核心作用。与p16INK4a及相关的p19INK4d结合的Cdk6结构显示，INK4抑制剂在催化裂隙的ATP结合位点旁结合，与激活的细胞周期蛋白亚基结合位点相对。它们通过引起传播至细胞周期蛋白结合位点的结构变化间接阻止细胞周期蛋白结合。INK4抑制剂还使激酶催化裂隙变形并干扰ATP结合，这解释了它们如何也能抑制预先组装的Cdk4/6-细胞周期蛋白D复合物。INK4a和Cdk4中的肿瘤衍生突变定位于界面接触，巩固了CDK结合和抑制在p16INK4a肿瘤抑制活性中的作用。
